Polysialic acid–neural cell adhesion molecule in brain plasticity: From synapses to integration of new neurons

B RA I N RE SE A R CH RE V I EW S 56 ( 20 0 7 ) 1 0 1–1 1 8

a v a i l a b l e a t w w w. s c i e n c e d i r e c t . c o m

w w w. e l s e v i e r. c o m / l o c a t e / b r a i n r e s r e v

Review

Polysialic acid–neural cell adhesion molecule in brain plasticity: From synapses to integration of new neurons Eduardo Gascon a , Laszlo Vutskits b , Jozsef Zoltan Kiss a,⁎ a

Department of Neuroscience, University of Geneva Medical School, 1, Rue Michel Servet, CH-1211, Geneva, Switzerland Department of Anesthesiology, Pharmacology and Intensive Care, University Hospital of Geneva, Geneva, Switzerland

b

A R T I C LE I N FO

AB S T R A C T

Article history:

Isoforms of the neuronal cell adhesion molecule (NCAM) carrying the linear homopolymer

Accepted 24 May 2007

of alpha 2,8-linked sialic acid (polysialic acid, PSA) have emerged as particularly attractive

Available online 4 July 2007

candidates for promoting plasticity in the nervous system. The large negatively charged PSA chain of NCAM is postulated to be a spacer that reduces adhesion forces between cells

Keywords:

allowing dynamic changes in membrane contacts. Accumulating evidence also suggests

Cell adhesion

that PSA–NCAM-mediated interactions lead to activation of intracellular signaling cascades

Learning and memory

that are fundamental to the biological functions of the molecule. An important role of PSA–

Synaptic plasticity

NCAM appears to be during development, when its expression level is high and where it

Neurogenesis

contributes to the regulation of cell shape, growth or migration. However, PSA–NCAM does persist in adult brain structures such as the hippocampus that display a high degree of plasticity where it is involved in activity-induced synaptic plasticity. Recent advances in the field of PSA–NCAM research have not only consolidated the importance of this molecule in plasticity processes but also suggest a role for PSA–NCAM in the regulation of higher cognitive functions and psychiatric disorders. In this review, we discuss the role and mode of actions of PSA–NCAM in structural plasticity as well as its potential link to cognitive processes. © 2007 Elsevier B.V. All rights reserved.

Contents 1. 2.

3.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . Molecular structure of PSA–NCAM . . . . . . . . . . . . . . 2.1. The NCAM core protein . . . . . . . . . . . . . . . . 2.2. The polysialic acid chain . . . . . . . . . . . . . . . PSA–NCAM signaling pathways . . . . . . . . . . . . . . . . 3.1. NCAM signaling through heterophilic interactions of 3.2. NCAM signaling through heterophilic interactions of 3.2.1. Interactions with the FGF receptor. . . . . . 3.2.2. NCAM as a co-receptor for GDNF . . . . . .

⁎ Corresponding author. Fax: +41 223795452. E-mail address: [email protected] (J.Z. Kiss). 0165-0173/$ – see front matter © 2007 Elsevier B.V. All rights reserved. doi:10.1016/j.brainresrev.2007.05.014

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . the intracellular domain . the extracellular domain. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

102 102 102 103 105 105 105 105 105

102

B RA I N R E SE A R CH RE V I EW S 56 ( 20 0 7 ) 1 0 1–1 1 8

3.3.

Newly identified partners of NCAM . . . . . . . . . . . . . . 3.3.1. NCAM and glutamate receptors . . . . . . . . . . . . 3.3.2. NCAM and neurotrophin receptors . . . . . . . . . . 3.4. Role of PSA in NCAM signaling . . . . . . . . . . . . . . . . . 4. Functions of PSA–NCAM in Brain plasticity . . . . . . . . . . . . . . 4.1. Synaptic plasticity . . . . . . . . . . . . . . . . . . . . . . . . 4.1.1. NCAM and synaptic consolidation . . . . . . . . . . 4.1.2. Setting the stage for plasticity . . . . . . . . . . . . . 4.2. Axonal and dendritic growth . . . . . . . . . . . . . . . . . . 4.3. Neurogenesis and recruitment of new neurons to functional 4.3.1. PSA–NCAM and neuronal precursor migration . . . . 4.3.2. Neuronal precursor differentiation . . . . . . . . . . 4.3.3. Survival of newly generated neurons . . . . . . . . . 5. PSA–NCAM and cognitive functions . . . . . . . . . . . . . . . . . . 6. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1.

Introduction

One of the most important challenges of current neurosciences is to understand cognitive functions at the level of molecular mechanisms. Modern theories of mental function propose that cognitive processes such as learning, memory, perception and consciousness require the continuous activityinduced remodeling of neuronal circuits (Albright et al., 2000; Purves and Andrews, 1997; Purves et al., 1994; Singer, 1986). This lifelong self-reorganization process in the brain requires the dynamic stabilization and destabilization of neuronal connectivity according to experience. Adaptive reorganization of neuronal connectivity that permits the acquisition of new information most likely involves a spectrum of modifications including the molecular remodeling of synapses leading to their strengthening/silencing, the formation of new synapses and destabilization of previously established contacts (Hebb and Konzett, 1949; Purves and Andrews, 1997; Purves et al., 1994). Mechanisms underlying cognitive function-associated plasticity most likely involve the same regulatory factors that control morphogenesis of neural networks during development (Edelman and Cunningham, 1990). Numerous candidate molecules have been identified during the last two decades for contributing to different plasticity processes (Edelman and Cunningham, 1990). Among these, isoforms of the neural cell adhesion molecule (NCAM) carrying an unconventional carbohydrate polymer, polysialic acid (PSA), are of particular interest. NCAM is a member of the immunoglobulin superfamily that is involved in cell surface recognition and can promote cell adhesion through a homophylic Ca2+-independent binding mechanism (Edelman, 1986). NCAM is traditionally viewed as a mediator of cell–cell interactions establishing a physical anchorage of cells to their environment. However, the attachment of the PSA chain to the NCAM protein core provides unique properties to the molecule. PSA has a large hydrated volume and high negative charge density and therefore, is well placed to attenuate adhesion forces and to negatively regulate overall cell surface interactions (Rougon, 1993; Rutishauser, 1996). The attach-

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . networks. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . .

106 106 106 106 107 107 108 109 109 109 110 110 110 111 113 113

ment of PSA to NCAM is a developmentally regulated process; NCAM with high PSA content is associated with morphogenetic changes during development such as cell migration, synaptogenesis and axonal growth, while in adult brain poorly sialylated forms of NCAM stabilize cell–cell contacts (Rougon, 1993; Rutishauser, 1996). Importantly, PSA–NCAM is retained in adult brain structures that display a high degree of structural plasticity and has emerged as a plasticity-promoting molecule in the adult nervous system (Kiss and Rougon, 1997). This unique function of PSA–NCAM within the CAM family is emphasized by its contribution to various adaptive processes including hippocampal long-term potentiation (LTP) (Muller et al., 1996), memory formation (Doyle et al., 1992a; Sandi et al., 2003), neuroglial plasticity in the hypothalamus (Theodosis et al., 2004), lesion-induced neural sprouting (Muller et al., 1994) and functional recovery (Troncoso et al., 2004). In this review, we summarize current knowledge on the role of PSA–NCAM in cognitive functions and the underlying plasticity processes. First, we will briefly review the structural characteristics and molecular partners of PSA–NCAM. Second, we will elaborate on the potential functions of PSA–NCAM in brain plasticity at the synaptic, cellular and network levels. Third, we will summarize recent evidences implicating PSA– NCAM in cognitive processes.

2.

Molecular structure of PSA–NCAM

2.1.

The NCAM core protein

The neural cell adhesion molecule (NCAM) was identified as a cell surface glycoprotein more than 30 years ago (Rutishauser et al., 1976). Early studies demonstrated that NCAM interacts with other NCAM molecules in the same (cis-interactions) or in opposing cell membranes (trans-interactions) (Rutishauser et al., 1982) and thereby identifying NCAM as a key mediator of cell adhesion in the central nervous system (CNS). NCAM is produced by a single gene that contains 20 major exons plus 6 additional small exons in the mouse (Walmod et al., 2004). Alternative splicing gives rise to several isoforms of

B RA I N RE SE A R CH RE V I EW S 56 ( 20 0 7 ) 1 0 1–1 1 8

NCAM named according to their apparent molecular weight (Fig. 1). NCAM-180 is a single pass transmembrane protein generated from exons 0–19; NCAM-140 differs from NCAM-180 only in exon 18 and it is also a transmembrane protein whose cytoplasmic domain is considerably shorter; NCAM-120 is a GPI anchored protein resulting from the transcription of exons 0–15. NCAM also exists in a secreted form produced when one of the small exons located between exons 12 and 13 is included in the mRNA. This small exon contains a stop codon and gives rise to a truncated form of NCAM (Walmod et al., 2004). Soluble forms of NCAM can also be generated by the enzymatic excision of NCAM-120 from the GPI anchor (He et al., 1986) or by the proteolytic cleavage of the extracellular part of NCAM molecules (Hinkle et al., 2006). Structurally, NCAM belongs to the superfamily of immunoglobulin proteins (Brummendorf and Rathjen, 1995). The extracellular domain of NCAM presents several identifiable motifs (Fig. 1): five Ig-homology modules (Ig I–V) followed by two fibronectin type III domains (denoted F3I and F3II). Current models for NCAM homophilic binding come from structural and functional studies (Kasper et al., 2000; Soroka et al., 2003) (Fig. 1). It seems that cis-interactions depend on aromatic residues located in the IgI module that are buried in a hydrophobic pocket formed in the IgII module (Soroka et al., 2003). On the other hand, trans-interactions require first the formation of NCAM cis-dimers. Two kinds of trans-interactions have been proposed for these dimers. The first one, known as

103

“flat zipper”, involves IgII to IgIII binding whereas the second, referred to as “compact zipper”, implicates the interaction between IgI–IgIII and IgII–IgII (Soroka et al., 2003; Walmod et al., 2004). NCAM is also capable to interact with a number of molecules in a heterophilic manner (Fig. 2). Thus, it has been shown that NCAM can bind other members of the Ig family of adhesion molecules such as L1 or TAG-1 (Brummendorf and Rathjen, 1995). In addition, NCAM interacts with several members of the extracellular matrix (ECM) including the glycosaminglycan heparin (Cole and Glaser, 1986), chondroitin sulfate proteoglycans such as phosphocan or neurocan (Milev et al., 1995; Retzler et al., 1996) and heparin sulfate proteoglycans (Storms et al., 1996). Of utmost importance are NCAM interactions with growth factor receptors. Doherty and Walsh demonstrated that NCAM could interact with and activate the fibroblast growth factor receptor (FGFR) (Doherty and Walsh, 1996). More recently, it has been found that the glial derived neurotrophic factor (GDNF) can signal independently from RET through a receptor complex formed by NCAM and GFRα (Paratcha et al., 2003).

2.2.

The polysialic acid chain

The NCAM protein core is submitted to several post-translational modifications (Fig. 1) (Walmod et al., 2004) but, functionally, glycosylation is by far the most important.

Fig. 1 – Molecular features of NCAM. (A) Schema illustrating the identifiable domains (left) and the post-translational modifications (right) found on the NCAM protein core. (B) Molecular structure of different NCAM isoforms. As illustrated in the picture, NCAM 180 and 140 are transmembrane proteins that only differ in a small portion of the intracellular domain. NCAM 120 contains the extracellular domain linked to the membrane through a GPI anchor. Finally, soluble NCAM results either from an alternative splicing or from the enzymatical removal of the extracellular domain of other NCAM isoforms. (C) The current model for NCAM interactions. As depicted, NCAM cis-dimers involve the interaction between IgI and IgII (red circle). NCAM trans-interactions require the initial formation of cis-dimers. Then, two kinds of interactions between NCAM molecules on opposing cell membranes are possible (Soroka et al., 2003). The “flat zipper” interaction, illustrated in the picture, involves IgII and IgIII domains (green circle). ECD: extracellular domain; TMD: transmembrane domain; ICD: intracellular domain: IgI–V: Ig-like domain I–V; F3I/II: fibronectin type 3 homology domain I/II.

104

B RA I N R E SE A R CH RE V I EW S 56 ( 20 0 7 ) 1 0 1–1 1 8

Fig. 2 – Molecular interactions and signaling of NCAM/PSA–NCAM. NCAM intrinsic signaling relies on the heterophilic interactions of the intracellular domain and mainly results in MAPK activation. NCAM extracellular domain interacts with a number of other proteins involved in cell adhesion such as ECM members or other CAMs (left). Importantly, the presence of PSA (right) allows NCAM to interact with diverse signaling molecules (glutamate receptors, tyrosine kinase receptors and p75…). Since many of these new partners are able to activate intracellular signaling cascades, it has been proposed that PSA might shift NCAM activity from an anchoring to a signaling state.

Glycosylation is a common modification of membrane and secreted proteins and carbohydrate residues have often a major impact on the three dimensional folding, stability and function of native proteins (Varki, 1993). NCAM undergoes extensive glycosylation in the ER and Golgi compartments (see references in Kiss and Rougon, 1997). N-glycosylation is largely the most important post-translational modification of NCAM molecule, albeit O-glycans can also be found on certain muscle specific isoforms (Ong et al., 2002; Walsh et al., 1989). At least 6 potential N-glycosylation sites (Asn 203, 297, 329, 415, 441 and 470) have been identified in the extracellular domain of NCAM (Albach et al., 2004). The main carbohydrate attached to NCAM is polysialic acid (PSA), a linear homopolymer of α2,8-linked sialic acid (Finne et al., 1983; Hoffman et al., 1982). PSA chains can extend to lengths of 50–100 units (Kiss and Rougon, 1997; Livingston et al., 1988) and are preferentially linked to Asn470 and to a lesser extent to Asn412 (Geyer et al., 2001; Von Der Ohe et al., 2002). Biochemical characteristics of polysialic acid mainly derive from carboxyl group of sialic acid and include bearing negative charge, covering large space and sustaining water and ionic

molecules. Due to its composition, PSA has been shown to attenuate NCAM–NCAM interactions and therefore interfere with cell adhesion (Kiss and Rougon, 1997; Rutishauser and Landmesser, 1996). The synthesis of PSA is catalyzed by two different polysialyltransferases, ST8Sia II and IV (Kojima et al., 1995; Nakayama et al., 1998; Tsuji, 1996). ST8Sia II and IV are members of the family of sialyltransferases that also include α2,3 and α2,6 sialyltransferases (Angata and Fukuda, 2003). The enzymes share ∼ 59% homology in the amino acid sequence and both have a short cytoplasmic segment and a large intraluminal domain containing a stem region and a catalytic domain. It has been recently shown that polysialyltransferase activity relies specifically on a 32 amino acid motif of the catalytic domain that is unique for α2,8 sialyltransferases (Nakata et al., 2006). Polysialylation is an atypical glycosylation as no more than 6 mammalian proteins have been found to contain PSA (Finne et al., 1983; Mendiratta et al., 2005; Rothbard et al., 1982). Remarkably, ST8Sia II and IV are able to polysialylate themselves and this autopolysialylation seems to be essential for proper activity of the enzyme on the

B RA I N RE SE A R CH RE V I EW S 56 ( 20 0 7 ) 1 0 1–1 1 8

target protein (Muhlenhoff et al., 2001). Cells producing PSA express both ST8Sia II and IV. Since the degree of polysialylation by ST8Sia II is lower (about 40 sialic acid residues) than that by ST8Sia IV (about 60 residues) (Angata et al., 2002; Kitazume-Kawaguchi et al., 2001), it has been proposed that these enzymes might work cooperatively and their simultaneous presence would result in higher levels and longer polymers of PSA (Angata and Fukuda, 2003). The expression of PSA on NCAM is tightly regulated and there is a peak of expression early in development followed by a progressive reduction that leads to the adult stage where most NCAM in the brain does not contain PSA. Nonetheless, some brain regions retain high levels of PSA expression during the adult life. These areas such as the hypothalamus, hippocampus or the olfactory bulb are associated with neural plasticity, remodeling of neural connections or neuronal generation (see references in Bruses and Rutishauser, 2001; Kiss and Rougon, 1997). Obviously, this pattern of PSA expression reflects the presence of active synthesizing enzymes. The translational and post-translational control of ST8Sia II and IV activity remains largely unknown (Angata and Fukuda, 2003).

3.

105

NCAM–spectrin–PKCβ2 was required for the neuritogenic effect of NCAM (Leshchyns'ka et al., 2003). In a recent work (Sytnyk et al., 2006), it has been reported that NCAM–spectrin interactions are also essential for the proper assembly, maintenance and activity-dependent remodeling of the postsynaptic signaling complex in excitatory synapses. NCAM is also known to stimulate the mitogen-activated protein (MAP) kinase pathway (Kolkova et al., 2000; Schmid et al., 1999) through the interaction with Fyn and FAK. Thus, NCAM–NCAM interactions have been shown to induce the phosphorylation of Fyn and FAK. Phosphorylated FAK can interact with a number of adaptor proteins such as Grb2 (Lin et al., 1997), Cas (Schaller, 2001) or Shc (Barberis et al., 2000) and, by this means, to recruit and activate several elements of the MAP kinase pathway including Ras (Lin et al., 1997) or Raf (Zhang et al., 2002). It is noteworthy that Fyn constitutively associates with NCAM whereas FAK seems to be recruited to the cell membrane only upon NCAM homophilic binding (Beggs et al., 1997). In fact, it has been shown that FAK does not directly interact with NCAM but with the SH2 domain of Fyn (He and Meiri, 2002). Altogether these data point to a model where Fyn would act as a “sensor” of NCAM homophilic binding to recruit FAK and initiate the intracellular cascade leading to MAP kinase activation.

PSA–NCAM signaling pathways

Intensive work during the last decades has expanded NCAM functions from a simple mediator of cell adhesion to a versatile transducing molecule participating in a broad range of biological process such as cell adhesion, synaptic plasticity, neurite outgrowth or migration (Kiryushko et al., 2003; Muller et al., 1996; Rutishauser et al., 1976; Zhang et al., 2004). Due to the absence of enzymatic activity, intracellular signaling through NCAM depends on the ability of NCAM to interact directly or indirectly with other molecules (Fig. 2). In this section, a brief summary of the “classical” molecular pathways activated by NCAM will be followed by an overview of recent work pointing to novel NCAM interactions. Finally, we will discuss how PSA might modulate these interactions.

3.1. NCAM signaling through heterophilic interactions of the intracellular domain Initial studies to unravel NCAM signaling pathways used immunoprecipitation (Beggs et al., 1997; Leshchyns'ka et al., 2003; Pollerberg et al., 1987) or ligand affinity chromatography (Buttner et al., 2003) to identify candidate molecules able to interact with the intracellular domain of NCAM. Only some of them have been found to participate in NCAM signaling including spectrin with the non-receptor tyrosine kinases Fyn (a member of the Src family) and the focal adhesion kinase (FAK) (Hinsby et al., 2004). Spectrin is a ubiquitous scaffolding protein that acts in conjunction with a variety of adaptor proteins to organize membrane microdomains (De Matteis and Morrow, 2000). Leshchyns'ka and colleagues showed that NCAM selectively interacts and complexes with the −NH2 terminus of βI spectrin and demonstrated that protein kinase Cβ2(PKCβ2) is recruited to these complexes through the pleckstrin homology domain of spectrin. Furthermore, they found that this interaction

3.2. NCAM signaling through heterophilic interactions of the extracellular domain 3.2.1.

Interactions with the FGF receptor

The first evidences that NCAM might interact with the FGFR came from pharmacological studies. It was demonstrated that a variety of pharmacological reagents including tyrosine kinase inhibitors, blockers of phospholipase Cγ (PLCγ), DAG lipase inhibitors and calcium channels antagonists, all inhibited both NCAM and FGFR-mediated neurite outgrowth (Doherty and Walsh, 1996). This hypothesis has received further support from subsequent studies: (i) homophilic NCAM interactions lead to the phosphorylation of FGFR (Williams et al., 1994); (ii) NCAM-dependent neurite outgrowth is impaired in neurons expressing a dominant negative form of the FGFR (Ronn et al., 1999) and (iii) NCAM directly interacts with and induces autophosphorylation of FGFR (Kiselyov et al., 2003). It is now well established that NCAM homophilic binding results in the dimerization and autophosphorylation of the FGFR. The intracellular cascade activated by the FGFR mainly involves the activation of phospholipase Cγ (PLCγ) that generates the second messengers, IP3 and diacylglycerol (DAG). The former is known to induce calcium release from internal stores whereas the latter remains at the cell membrane where it is cleaved by DAG lipase to give rise to arachidonic acid (AA) and 2-arachidonylglycerol (2-AG). It seems that the neurite outgrowth depends on the ability of 2AG to activate cannabinoid receptors 1 and 2 (CB1 and CB2) (Williams et al., 2003).

3.2.2.

NCAM as a co-receptor for GDNF

It has been recently described that NCAM acts as a signaling receptor for members of the GDNF family (Paratcha et al., 2003). These findings were rather unexpected as GDNF

106

B RA I N R E SE A R CH RE V I EW S 56 ( 20 0 7 ) 1 0 1–1 1 8

intracellular signaling was thought to be mediated through a complex formed by the RET receptor and members of the GDNF family receptor α (GFRα) (Durbec et al., 1996). RET is thought to be the signaling element of the complex as it possess a tyrosine kinase activity whereas the GPI-anchored GFRα is believed to be directly involved in ligand binding (Durbec et al., 1996). Strikingly, expression of GFRα in the nervous system is much broader than that of RET (Trupp et al., 1999) suggesting that GFRα can signal independently from RET. Using a biochemical approach, Paratcha et al. (2003) demonstrated that NCAM can bind to GDNF and that this interaction is potentiated in the presence of GFRα. Furthermore, they showed that GFRα directly complexes with NCAM thereby downregulating NCAM homophilic interactions. These interactions might be physiologically relevant as migration of Schwann cells and axonal growth of primary hippocampal neurons was stimulated by GDNF via NCAMGFRα. It is important to note that GDNF-NCAM-GFRα activity was transduced independently from FGFR through the Fyn– FAK–MAP kinase pathway.

(2000a) where it was shown that the defects in LTP observed in hippocampal slices prepared from NCAM knockout mice could be reversed by the exogenous application of BDNF. Subsequent work extended this notion to other biological process such as neuronal survival (Vutskits et al., 2001). These results suggested that PSA–NCAM was necessary for proper neurotrophin signaling and pointed to Trk receptors as most likely mediators. However, very recent data reported by two independent groups suggested that absence of PSA–NCAM in septal neurons (Burgess and Aubert, 2006) or in newly generated neuron from the subventricular zone (Gascon et al., 2007) mainly results in enhanced p75 signaling. Since p75 is known to interact with a number of proteins at the cell membrane (Costantini et al., 2005; Wang et al., 2002), one could envisage an interaction between PSA–NCAM and p75. Interestingly, Gascon et al. (2007) demonstrated that the absence of PSA–NCAM in vitro as well as in vivo led to an upregulation of p75 expression. Thus, PSA– NCAM signaling could modulate p75 signaling by controlling its expression.

3.4. 3.3.

Newly identified partners of NCAM

3.3.1.

NCAM and glutamate receptors

PSA–NCAM is known to be enriched at the postsynaptic sites where it can modulate synaptic transmission (Kiss et al., 2001; Muller et al., 1996). Two recent reports indicate that PSA– NCAM is able to directly interact with both AMPA and NMDA glutamate receptors (Hammond et al., 2006; Vaithianathan et al., 2004). In a series of elegant experiments using glutamate receptors reconstituted in artificial lipid bilayers, the authors compared the currents elicited by glutamate on different ionotropic receptors in the presence or absence of PSA–NCAM. It was found that PSA–NCAM profoundly modified glutamate responses: (i) it inhibited NMDA receptor currents (Hammond et al., 2006); but (ii) it prolonged the open channel time of AMPA receptor-mediated currents by several fold and altered the bursting pattern of the receptor channels (Vaithianathan et al., 2004). These data have been confirmed in hippocampal cultures (Hammond et al., 2006; Vaithianathan et al., 2004). Together, these results suggest a direct interaction between PSA–NCAM and the AMPA receptor itself raising the intriguing possibility that high expression of PSA–NCAM during development would play a major role in synapse formation by regulating glutamate receptor activity.

3.3.2.

NCAM and neurotrophin receptors

Neurotrophins represent a family of secreted proteins known to profoundly affect neuronal survival, differentiation, growth and plasticity (Miller and Kaplan, 2001). Four members of the neurotrophin family, nerve growth factor (NGF), brain derived neurotrophic factor (BDNF), neurotrophin 3 (NT3) and neurotrophin 4/5 (NT 4/5), have been identified in mammals. They exert their biological functions through two kinds of receptors: high affinity receptors belonging to the family of tyrosine kinase receptor family (Trk receptors) (Barbacid, 1994; Huang and Reichardt, 2003) and a low affinity receptor of the TNF receptor family (p75 receptor) (Chao, 1994; Nykjaer et al., 2005). The first evidence suggesting that PSA–NCAM interacts with neurotrophin signaling came from a study of Muller et al.

Role of PSA in NCAM signaling

One of the most striking features of NCAM functions is the apparent duality between NCAM and PSA–NCAM functions. As mentioned above, PSA levels are high during brain development, whereas, in the adult brain, PSA–NCAM is restricted to areas associated with morpho-functional plasticity (Kiss and Rougon, 1997; Kiss et al., 2001). Indeed, cellular processes observed in these regions of the adult brain (neuronal migration, neurite development or synaptic remodeling) are similar to those occurring in the developing brain suggesting that NCAM might support a different set of functions depending on PSA content. This idea has received further support from the analysis of transgenic animals lacking NCAM or polysialyl transferases. NCAM knockout animals present only minor defects in brain development and behavior (Cremer et al., 1994; Tomasiewicz et al., 1993). This mild phenotype is mostly related to defects in brain regions retaining PSA expression in the adulthood and could be mimicked by the enzymatic removal of PSA (Muller et al., 1996; Ono et al., 1994). These observations indicate that the absence of PSA accounts for the deficits observed in NCAM mutant animals and that compensatory mechanisms might exist to counteract this lack of PSA during development but not in the adult life. New insights into the specific functions of PSA have been obtained by the generation of ST8Sia II- and IV-deficient mice (Angata et al., 2004; Eckhardt et al., 2000). Since PSA can be synthesized by both enzymes, single knockout animals still produce PSA–NCAM. For this reason, it was not surprising that these mice exhibited only discrete neurological deficits. Interestingly, recent work reported severe abnormalities of brain development in double knockout animals (Weinhold et al., 2005). This includes not only the defects detected in NCAM knockout animals but also additional unique malformations mainly involving brain fiber tracts. Furthermore, using triple knockout animals (ST8Sia II−/−, ST8Sia IV−/−, NCAM−/−), Weinhold et al. (2005) showed that these additional defects were reversed by deletion of NCAM suggesting that they are originated by NCAM gain of function. These observations

B RA I N RE SE A R CH RE V I EW S 56 ( 20 0 7 ) 1 0 1–1 1 8

indicate that timely expression of PSA is required for brain development and highlight the importance of a strict NCAM homeostasis in this process. While the ability of PSA to modify NCAM functions is well established, the mechanism of this effect remains poorly understood. PSA does not seem to influence the ability of NCAM to bind GDNF-GFRα (Paratcha et al., 2003). In contrast, proper neurotrophin signaling is known to require PSA expression (Burgess and Aubert, 2006; Muller et al., 2000a) but the molecular interactions and intracellular pathways by which PSA–NCAM might control these signaling are still unknown. Similarly, the presence of PSA appears to be required for activating FGFR signaling (Dityatev et al., 2004). How PSA might influence FGFR or non-tyrosine kinase receptors is a subject of speculations. In the prevailing view of PSA–NCAM functions, the large negatively charged PSA chain is considered as a spacer that reduces adhesion forces between cells allowing dynamic changes in membrane contacts. It has been proposed that the PSA chain may modify the kinetic of NCAM homophilic binding in such a way that NCAM aggregation is reduced in the presence of PSA (Hinsby et al., 2004). PSA may also modify the strength and stability of other adhesion systems (Bruses and Rutishauser, 2001). It is of particular interest that the physical spacer function of PSA may also play a crucial role in growth factor receptor signalization. NCAM/PSA–NCAM most likely activates tyrosine kinase receptors such the FGFR through inducing dimerization and clustering of receptors (Kiselyov et al., 2005; Kiss et al., 2001). The firm adhesion mediated by unpolysialylated NCAM through strong two-dimensional zipper formation probably excludes interactions between NCAM and FGFR (Kiselyov et al., 2005). In contrast, the formation of loose clusters of onedimensional zippers in the presence of PSA favors the association between NCAM and FGFR (Kiselyov et al., 2005). Thus, the expression of PSA on NCAM may switch NCAM functions from adhesion to signaling. Consistent with this idea, the expression of PSA appears to be required for NCAMinduced FGFR signaling (Dityatev et al., 2004) and PSA was shown to increase cell responses to diverse growth factors including BDNF (Muller et al., 2000a; Vutskits et al., 2001), PDGF (Zhang et al., 2004) and CNTF (Vutskits et al., 2003).

4.

Functions of PSA–NCAM in Brain plasticity

Animal studies have shown that cortical representations are capable of a remarkable degree of plasticity under the influence of sensory or environmental stimulation throughout life (Buonomano and Merzenich, 1998). There are changes in cortical reorganization that take place rapidly, over periods of hours, and that probably depend upon properties of synaptic plasticity. Mechanisms such as long-term potentiation (LTP) or long-term depression (LTD) have been postulated to underlie cortical map re-organization (Kilgard and Merzenich, 1998; Kirkwood et al., 1996). On a slower time course, other properties such as axonal and collateral sprouting, dendritic elongation and branching may also be involved (Florence et al., 1998). A particularly interesting aspect of adult plasticity is the recruitment of new neurons to functional networks. The persistent lifelong neurogenesis in the hippocampal formation

107

appears to be modified by experience and exercise and has been implicated in learning and memory (Aimone et al., 2006; Ming and Song, 2005). In the following section, we summarize recent data regarding the functions of PSA–NCAM in three key aspects of structural plasticity: (1) synapse formation and remodeling; (2) axonal/dendritic growth and retraction; (3) neuronal replacement in the postnatal brain.

4.1.

Synaptic plasticity

Synaptic plasticity, including LTP and LTD, has been defined as activity-induced lasting changes in synaptic strength (Bliss and Collingridge, 1993). These modifications in synaptic properties reflect a continuum of synaptic changes going from subtle alterations in the efficacy of synaptic transmission to distinct structural reorganization of connections (Muller et al., 2000b; Yuste and Bonhoeffer, 2001). Extensive evidence indicates that much of this plasticity occurs at dendritic spines, the postsynaptic sites of excitatory connections (Yuste and Bonhoeffer, 2001). Plasticity related events could include changes in receptor composition at the postsynaptic site, enlargements of synaptic surfaces or spines, the formation perforated synapses, bifurcation of spines and the formation of new spines and synapses (Muller et al., 2000b; Yuste and Bonhoeffer, 2001). LTP is typically induced by highfrequency stimulation (HFS) of excitatory input leading to rapid calcium influx in postsynaptic dendritic spines via NMDA receptors. The maintenance of LTP involves an early phase of rapid, covalent modification of existent proteins and a late phase that is associated with mRNA and protein synthesis (Kelleher et al., 2004; Malenka and Bear, 2004; Nguyen and Kandel, 1996). Several groups reported that interference with NCAM and PSA–NCAM could alter CA1 LTP in the hippocampus without affecting basal synaptic transmission (Becker et al., 1996; Cremer et al., 1998; Luthi et al., 1994; Muller et al., 1996; Ronn et al., 1995). These results were obtained with antibodies directed against the NCAM molecule (Luthi et al., 1994; Ronn et al., 1995), in transgenic mice lacking the NCAM gene (Cremer et al., 1998; Muller et al., 1996) and after specific removal of PSA from NCAM with the enzyme Endo-N (Becker et al., 1996; Muller et al., 1996). Most importantly, the deficient LTP observed in the NCAM KO animal has been confirmed in conditionally NCAM-deficient mice, in which the NCAM gene was ablated in excitatory neurons postnatally after the cessation of major developmental events (Bukalo et al., 2004). Thus, the deficit in CA1 LTP in constitutively NCAMdeficient mice is not a consequence of developmental abnormalities but the result of dysfunction of the NCAM glycoprotein in mature synapses. The fact that elimination of PSA from NCAM by Endo-N treatment reversibly prevents LTP induction (Becker et al., 1996; Muller et al., 1996) suggested that PSA or the balance between PSA–NCAM and NCAM could represent an important factor. More recently, this issue was addressed using mice deficient in ST8SiaIV (Eckhardt et al., 2000). These mice expressed NCAM but exhibited considerably lower levels of PSA–NCAM in the hippocampus. When testing synaptic plasticity, it appeared that, at Schaffer collateral-CA1 synapses, where PSA is normally expressed in wild type animals, LTP was impaired in a similar way as in NCAM

108

B RA I N R E SE A R CH RE V I EW S 56 ( 20 0 7 ) 1 0 1–1 1 8

knockout mice. In contrast, LTP was unaffected at mossy fiberCA3 synapses, which do not normally express PSA–NCAM in the adult. As elimination of NCAM still prevented induction of normal LTP in this system, a possibility is that NCAM plays a more important role at these synapses. Consistent with this, polysialyltransferase-deficient mice did not show the morphological deficit in mossy fiber innervation reported in NCAM knockout mice. Thus, it is not unlikely that the relative contribution of NCAM and PSA–NCAM to synaptic plasticity may vary at different types of synapses, the balance between the two forms of the molecule representing again an important factor (Fig. 3).

4.1.1.

NCAM and synaptic consolidation

The critical question is how and where NCAM/PSA–NCAM affects synaptic plasticity. The most plausible function of NCAM/PSA–NCAM in this process is related to the dynamic balance between stability and plasticity of synaptic connections; firm adhesion and stabilization of membrane contacts are associated with the presence of the non-polysialylated NCAM and loose contacts and plasticity are promoted by PSA– NCAM (Fig. 3). This scenario is consistent with the developmental expression pattern of NCAM/PSA–NCAM in axons and synapses; PSA is expressed on axons and dendrites before contact formation but it appears to be rapidly downregulated once synaptic contacts are established (Bruses et al., 2002). Recent in vitro experiments using heterogenotypic cultures of NCAM positive and negative hippocampal neurons (Dityatev et al., 2000) suggest that NCAM could play a crucial role in the

initial formation and stabilization of synapses. In this model, preferential formation and stabilization of synapse were found between NCAM expressing cells. The authors also determined that postsynaptically but not presynaptically expressed NCAM plays a crucial role in determining synapse formation and stability. Interestingly, such a role could be demonstrated only in excitatory synapses and not in GABAergic inhibitory synapses (Dityatev et al., 2000). Thus, the presence of NCAM on spines may thus be important for a proper formation and functioning of the synapse. Using the same in vitro model, Sytnyk et al. (2002; 2004) demonstrated that NCAM is recruited to axodendritic contacts within minutes after initial contact formation. This trafficking of NCAM to the synapse appears to involve organelles of the trans Golgi network (TGN) (Sytnyk et al., 2002); an observation that is consistent with the results showing that NCAM plays a role in the mobilization and cycling of synaptic vesicles at the neuromuscular junction (Polo-Parada et al., 2001). Anchoring TGN organelles to synapses is reduced in NCAM-deficient neurons suggesting that NCAM contributes to the anchoring of intracellular organelles to nascent synapses. NCAM takes part in the spectrin-based scaffold in the postsynaptic density (PSD) and it promotes accumulation of spectrin in PSDs (Pollerberg et al., 1986; Sytnyk et al., 2002, 2006). Work from Schachner's lab also indicates that NCAM 180 but not 140 is linked to spectrin in TGN organelles (Sytnyk et al., 2002). Spectrin binds to the C-terminal part of NMDA receptor subunits NR1 and NR2B, but not the AMPA receptor subunits GluR1 and GluR2/3, as well as to other kinases and

Fig. 3 – Putative functions of NCAM/PSA–NCAM in synaptic remodeling/stabilization. Stable synapses (left) contain predominantly non-sialylated NCAM (180 kDa) that contributes to the proper recruitment and arrangement of synaptic proteins. Activation that induce synaptic plasticity might result in an increased expression of PSA–NCAM in the synapse. PSA–NCAM at the cell surface might promote synaptic remodeling (center) by (i) reducing adhesion forces and therefore allowing membrane expansion/retraction; (ii) shifting NCAM from an anchorage to a “signaling” activity and (iii) by affecting glutamate channels responses. In a final step, the synapse might stabilize its new conformation by favoring NCAM expression. In this model, the balance between NCAM and PSA–NCAM acts as “an activity sensor” and might be critical to regulate activity-dependent structural modifications at the synaptic level.

B RA I N RE SE A R CH RE V I EW S 56 ( 20 0 7 ) 1 0 1–1 1 8

phosphatases such as CaMKIIα, a key player of LTP (Bodrikov et al., 2005; De Matteis and Morrow, 2000; Wechsler and Teichberg, 1998). Assembly of these components at the synapse is impaired in NCAM−/− mice and reduced in NCAM +/+ synapses by a dominant negative spectrin fragment containing the NCAM-binding site or when βI spectrin expression is reduced by using siRNA technology (Sytnyk et al., 2006). Reduced accumulation of spectrin and NMDA receptors in NCAM−/− PSDs results in an inability to recruit CaMKIIα to synapses in an activity-dependent manner that is required for longer lasting changes in synaptic strength (Sytnyk et al., 2006). Together, these results give strong support to the hypothesis that NCAM plays a central role in recruiting organelles and molecular components to sites of synaptic contacts and thereby contributing to the formation and consolidation of the synapse. This mechanism could serve in the consolidation of synapses during synaptogenesis as well as in late phases of LTP.

4.1.2.

Setting the stage for plasticity

How does PSA fit into this scenario? One possibility is that during the initial phase of synaptic plasticity highly polysialylated NCAM is rapidly transported to synaptic contacts. As illustrated in Fig. 3, the increased concentration of PSA at or around the synapse could function as a spacer modifying adhesion forces by changing cis-, homophilic or heterophilic interactions of NCAM in the membrane. This could result in reduced adhesion forces between opposing membranes thus allowing plasticity (Rutishauser et al., 1988; Rutishauser and Landmesser, 1996). This hypothesis is consistent with the observation that neuronal activity and NMDA receptor activation play a role in the translocation of PSA–NCAM to the cell surface (Muller et al., 1996; Wang et al., 1996). In addition to regulating adhesion strength, recent experiments suggest that PSA–NCAM in synaptic plasticity could also act through modifications of intracellular signaling including BDNF signaling through TrkB receptors, FGF receptor as well as glutamate receptor signaling (Dityatev et al., 2004; Kiselyov et al., 2005; Kiss et al., 2001; Muller et al., 2000a). Regardless of precise mechanism, the increased expression of PSA in synapses may play a permissive role allowing the expression of instructive signaling for plasticity and structural remodeling.

4.2.

Axonal and dendritic growth

Remodeling of dendritic and axonal arbors including branch formation/elimination as well as collateral branching has been implicated in network plasticity associated with cognitive functions as well as in brain repair. Based on its role in regulating neural network development and repair, NCAM/ PSA–NCAM could play a role in this process. Through selective elimination of PSA on NCAM by the enzyme Endo-N, it has been possible to demonstrate in many different systems that PSA–NCAM plays a role in nerve fasciculation, axon branching and formation of synapses (Bonfanti, 2006; Kiss and Rougon, 1997; Rutishauser and Landmesser, 1996). Removal of PSA on NCAM was found to alter fiber–target interactions and the arborization of sensory axons in the otic epithelium (Hrynkow et al., 1998), it was associated with projection errors of ganglion cells in the retina (Monnier et al., 2001), aberrant

109

mossy fiber innervation and ectopic synaptic boutons in the hippocampus (Seki and Rutishauser, 1998) and alteration of axon branching and the laminar organization of thalamocortical inputs (Yamamoto et al., 2000). In the central nervous system, PSA–NCAM appears to label sprouting fibers. For example, PSA expression is increased in the corticospinal system when collateral branches begin to form at the level of the brain stem (Daston et al., 1996). After removing PSA with Endo-N, the formation of cortico-spinal tract axon collaterals is strongly reduced. Saegusa et al. (2004) reported that amygdaloid-kindling increases PSA–NCAM positive immunoreactive mossy fibers in the dentate gyrus. PSA and L1 are upregulated on regenerating cholinergic axons during axonal elongation and downregulated upon target innervation (Aubert et al., 1998). Knocking down ST8SiaII expression by RNA interference resulted in significantly reduced neurite outgrowth (Brocco and Frasch, 2006). In a recent study, Franz et al. (2005) explored the role of PSA–NCAM in motoneuron regeneration after peripheral axon damage. In this model, regenerating axons can choose between reinnervating motor as well as cutaneous targets. Wild type axons carrying both NCAM and PSA–NCAM preferentially reinnervate their appropriate muscle target(s). This innervation pattern was perturbed in NCAM-deficient mice or when PSA was removed enzymatically. This type of regeneration requires axonal sprouting and pruning of misguided axons. It appears that the absence of PSA prevents normal sprouting and results in the occurrence of misprojecting axons. All these examples indicate therefore that the expression of PSA–NCAM during development as well as in adult plasticity could participate in regulating axonal growth and sprouting (Franz et al., 2005).

4.3. Neurogenesis and recruitment of new neurons to functional networks While current theories attribute a pivotal role to synaptic plasticity in cognitive functions, another type of plasticity, recruitment of new neurons to functional circuits has emerged as an intriguing complementary mechanism. Neural stem/progenitors cells (NPCs) have been isolated from most regions of the postnatal mammalian brain (Altman, 1962; Dayer et al., 2005; Gould et al., 1999). However, neurogenesis in the context of active cell replacement program occurs only in 2 restricted areas, the subventricular zone of the lateral ventricule (SVZ) (Alvarez-Buylla et al., 2000) and the subgranular zone of dentate gyrus (SGZ) in the hippocampus (Kempermann and Gage, 2000). The exact physiological relevance of adult neurogenesis is not yet clear. Neurogenesis in the dentate gyrus was shown to change by enriched environments, exercise and hippocampus-dependent learning tasks (Gould and Tanapat, 1999; Kempermann et al., 1997; Van Praag et al., 1999). Consequently, it has been proposed that integration of new neurons into functional circuits might be involved in learning and memory processes (Aimone et al., 2006). Neurogenesis in the SVZ and recruitment of new neurons into olfactory circuits was suggested to be important for sensory discrimination (Lledo et al., 2006). In both neurogenic regions, adult type stem cells and their progeny are localized in specific neural niches (Doetsch, 2003; Palmer et al., 2000) that provide a specific microenvironment

110

B RA I N R E SE A R CH RE V I EW S 56 ( 20 0 7 ) 1 0 1–1 1 8

where stem cells replenish themselves through self-renewal and give rise to different progenies through asymmetric divisions. Newborn neurons migrate away from the neurogenic niche and integrate into the circuits of the olfactory bulb and dentate gyrus. NCAM and PSA–NCAM expression is a characteristic feature of the postnatal neurogenic sites (Garcia-Verdugo et al., 1998; Rousselot et al., 1995). The available evidence indicates that, in the SVZ niche, PSA– NCAM is specifically expressed in committed neuronal precursors but not in GFAP positive stem cells or transit amplifier cells (Garcia-Verdugo et al., 1998; Ming and Song, 2005). The situation is similar in the SGZ niche though PSA–NCAM expression was also found in proliferating transit amplifier cells (Ming and Song, 2005). In the subventricular zone/ olfactory system, strong PSA–NCAM expression was found in migrating neuroblast and its expression progressively downregulated in the olfactory bulb (Ono et al., 1994).

4.3.1.

PSA–NCAM and neuronal precursor migration

The functional significance of PSA on NCAM in adult neurogenic zones is incompletely understood. Genetic deletion of the NCAM molecule (NCAM−/−) results in about 30% decrease in the size of the OB, while the overall brain size is reduced by about 10% (Cremer et al., 1994; Tomasiewicz et al., 1993). These defects can be duplicated by the injection of Endo-N, an enzyme that specifically cleaves the PSA moiety associated with NCAM, suggesting that the observed phenotypical changes in the NCAM−/− animal are primarily related to the absence of the PSA chain itself (Ono et al., 1994). Parallel to the reduction of OB size, an increased number of neuronal precursors are observed in the SVZ-RMS of NCAM−/− animals compared to wild type (WT) littermates (Chazal et al., 2000; Ono et al., 1994). It has been suggested that this accumulation of neuroblasts in the SVZ-RMS is the result of impaired chain migration of these cells toward the OB (Hu et al., 1996; Ono et al., 1994). The mechanism by which PSA–NCAM might influence neuroblast migration remains unknown. It has been proposed that PSA at the cell surface is required for weak adhesive interactions that would allow cell motility (Ono et al., 1994). In this respect, it has been shown that PSA–NCAM is not essential for cell locomotion in oligoendrocyte progenitor cells (OPCs) indicating that this molecule is not a component of the basic cellular machinery for movement/ adhesion (Zhang et al., 2004). These experiments also revealed that PSA–NCAM is required for the OPCs directional migration in response to concentration gradients of PDGF. Most interestingly, removal of PSA significantly reduced lamellipodia formation in response to low concentrations of PDGF, raising the possibility that under these conditions OPCs are less responsive to PDGF. These observations raised the intriguing possibility that PSA–NCAM could modify the ability of cells to sense accurately growth factor gradients. This hypothesis is consistent with previous studies demonstrating that the PSA chain of NCAM is required for adequate responses of neurons to BDNF (Muller et al., 2000a; Vutskits et al., 2001) and CNTF (Vutskits et al., 2003).

4.3.2.

Neuronal precursor differentiation

More recent data suggest that the migration deficit in the absence of PSA–NCAM may not be the whole story, and the

absence of PSA from the surface of neuroblasts may also influence the differentiation and the survival of newly generated neurons. According to a recent report, application of Endo-N into the rostral migratory zone results in a large number of process bearing cells (Petridis et al., 2004). This premature differentiation of neuroblasts in the absence of PSA is consistent with in vitro results showing an accelerated neurite outgrowth from neuroblastoma cells after removing PSA (Seidenfaden et al., 2003, 2006). The early differentiation after removing PSA has been attributed to NCAM-NCAM interactions (Petridis et al., 2004). However, this hypothesis is difficult to be reconciled with fact that such differentiation profile was recently demonstrated in the NCAM knockout animal (Gascon et al., 2007).

4.3.3.

Survival of newly generated neurons

The role of PSA–NCAM in newly generated neurons has been addressed in an in vitro model of neurogenesis (Vutskits et al., 2006). It has been demonstrated that removal of the polysialic tail of NCAM by Endo-N dramatically decreases the number of newly generated neurons. Similar results were obtained when PSA was blocked by a specific antibody and in cultures prepared from the NCAM−/− mice (Vutskits et al., 2006). Using pulse-chase labeling of neuronal progenitors with the proliferation marker BrdU, it was possible to differentiate between two distinct although closely related events of neurogenesis, namely the mitotic activity per se and the early survival of newly generated neurons (Vutskits et al., 2006). The evidence indicates that the lack of PSA–NCAM or NCAM does not influence mitotic activity, but rather it increases early cell death of newly generated immature neurons. These observations are in agreement with earlier reports showing that proliferation of neuronal progenitors in the postnatal subventricular zone is not affected in the NCAM −/− animals or in animals treated with Endo-N (Ono et al., 1994). They are also consistent with previous data demonstrating that interfering with PSA–NCAM affects the survival of neurons in dissociated (Vutskits et al., 2001) and organotypic cultures (Vutskits et al., 2003). Most importantly, it has been recently shown that apoptosis is increased nearly threefold in the SVZ and RMS of NCAM knockout animals versus wild types (Gascon et al., 2007). The enhanced rate of apoptotic cell death was cell specific since it occurred in the population of migrating neuroblasts (PSA+NCAM+) but not in GFAP positive astrocytes (PSA−NCAM+), supporting the hypothesis that PSA– NCAM and not NCAM is important for cell survival. This hypothesis received further support from in vitro experiments demonstrating that enzymatic removal or antibody blocking of PSA produce a significant increase in TUNEL labeling (Gascon et al., 2007). How PSA–NCAM might influence the survival newly generated neurons? One possibility is that BDNF signaling through Trk B receptors was impaired in the absence of PSA– NCAM (Muller et al., 2000a; Vutskits et al., 2001). Indeed, the survival promoting effects of BDNF were significantly less in Endo-N treated and NCAM−/− cultures than in control preparations (Gascon et al., 2007). Another, very interesting possibility is that PSA–NCAM influences the low affinity neurotrophin receptor p75 signaling. The first evidence for this is related to the fact that SVZ derived neurons in culture

B RA I N RE SE A R CH RE V I EW S 56 ( 20 0 7 ) 1 0 1–1 1 8

express p75, TrkB, TrkC but not TrkA, the high affinity receptor for NGF (Gascon et al., 2005). In vitro, NGF significantly increased apoptosis in cells lacking PSA suggesting that this effect is mediated through p75. In agreement with these results, pharmacological blockade of p75 but not Trk receptors, prevented neuronal cell death induced by the removal of PSA. It has also been demonstrated that the inhibition of two wellestablished pro-apoptotic cascades downstream of p75, ceramide and c-Jun N-terminal kinase (Barrett et al., 1998; Casaccia-Bonnefil et al., 1996; Dobrowsky et al., 1994; Frago et al., 1998; Hirata et al., 2001), completely prevented neuronal cell death induced by the absence of PSA in control as well as NGF treated cultures. Together, these data raised the possibility that the removal of PSA from NCAM induced an enhanced activation of p75 signaling pathways. In agreement with this idea, it was found that both in vivo and in vitro, immature neurons lacking PSA–NCAM express significantly higher levels of p75 than control cells. However, definitive evidence for this hypothesis would require further experiments involving the use of p75 knockout animals and function blocking antibodies. The fact that PSA removal did not affect TrkB or TrkC expression illustrates the specificity of this effect.

5.

PSA–NCAM and cognitive functions

Cognitive functions rely on the dynamic activity-dependent remodeling of neuronal networks. Since PSA–NCAM plays a major role in brain plasticity (see above), it is not surprising that those brain regions retaining high PSA–NCAM expression in the adult animal are known to be of utmost importance in different aspects of learning and memory processing (Bonfanti et al., 1992; Nacher et al., 2002; Varea et al., 2005). Analysis of postmortem human brain tissues also suggests an intriguing causal link between PSA–NCAM and cognitive functions as patients presenting cognitive deficits exhibit important alterations in the expression pattern of PSA–NCAM compared to control subjects. In Alzheimer's disease, a significant increase in PSA–NCAM expression has been found in the hippocampal formation of affected individuals and this was associated with the disorganization of PSA–NCAM-immunoreactive fibers in this region (Mikkonen et al., 1999). In line with these results, recent data indicate an increase in PSA–NCAM immunoreactivity on both neurons and glial cells in the hippocampus of chronic heroin addicts, a pathology known to be associated with cognitive deficits (Weber et al., 2006). Increased PSA– NCAM expression has also been reported in the hippocampus and entorhinal cortex of patients with drug-refractory temporal lobe epilepsy (Mikkonen et al., 1998). In contrast, an important decrease in the number of PSA–NCAM positive cells has been found in the hippocampal dentate gyrus in schizophrenic patients (Barbeau et al., 1995). In addition to human neuropathological observations, accumulating experimental evidence suggests a potential role for PSA–NCAM in different aspects of cognition. The majority of these studies focused on the hippocampus as much is known about the function of this brain structure in the context of learning and memory both in animals and humans (Squire et al., 1993). Several behavioral tests, associated with specific forms of hippocampus-related learning,

111

have been designed to detect possible dysfunction of this system. Amongst them, the passive avoidance learning paradigm is believed to rely on both hippocampus-dependent contextual memory and amygdala-dependent emotional memory (Gerlai, 2001). In the adult rat, the acquisition and the consolidation of the passive avoidance response have been shown to be associated with a transient increase in the sialylation of the NCAM180 in hippocampal membrane fractions, providing the first experimental indications on the involvement of PSA–NCAM in learning and memory formation (Doyle et al., 1992a). Immunocytochemical analysis then revealed a time-dependent increase in the number of PSA– NCAM positive neurons at the border of the granule cell layer and the hilus in the dentate gyrus following task acquisition (Fox et al., 1995). As early as 4 h following training, the amount of PSA–NCAM in these abovementioned regions was significantly increased on granule neurons and reached its maximum intensity about 12 h after exposure to the passive avoidance paradigm. Importantly, increased PSA levels did not persist subsequent to learning and returned to close pretraining levels 24 h following avoidance learning (Fox et al., 1995). Learning-associated increases in the number of PSA–NCAM positive neurons in the dentate gyrus are not unique to the nonspatial passive avoidance paradigm. Similar transient and time-dependent activation of dentate neuronal polysialylation status has been observed in rodents using the Morris water maze test, evaluating hippocampal-dependent spatial learning abilities (Morris et al., 1982; Murphy et al., 1996; Van der Borght et al., 2005; Venero et al., 2006) as well as applying a reward-based odor discrimination task that provides information on consolidation of olfactory memory within the hippocampus (Foley et al., 2003a). Altogether, these observations suggest that the temporary increased polysialylation of NCAM could be a universal feature of both spatial and nonspatial hippocampus-dependent learning tasks. Additionally, repetitive learning trials in the same animal, although improved performance and resulted in repetitive transient increases in the amount of PSA–NCAM, did not increase the overall magnitude of NCAM polysialylation state, suggesting that the immediate post-training activation of PSA expression may be related to the learning event rather than contributing to previously stored, task-associated memory retrieval (Murphy et al., 1996; Murphy and Regan, 1999). Given the intimate association between different hippocampus-dependent learning paradigms and the regulation of PSA–NCAM expression, an important question is whether interference, using pharmacological and genetic approaches, with this cell adhesion molecule can affect learning and memory consolidation. Intraventricular injections of antibodies and synthetic peptide ligands, interacting specifically with NCAM, have been shown to affect exploratory behavior and memory in rodents (Doyle et al., 1992b; Hartz et al., 2003). In line with these results, bath application of NCAM antibodies to hippocampal slice cultures impaired LTP (Luthl et al., 1994). Further insights into the potential link between PSA–NCAM and cognitive functions were obtained by the generation of mice where the NCAM gene was inactivated (Cremer et al., 1994). These animals show deficits in spatial learning when tested in the Morris water maze and a decaying LTP in the

112

B RA I N R E SE A R CH RE V I EW S 56 ( 20 0 7 ) 1 0 1–1 1 8

hippocampus (Cremer et al., 1994; Muller et al., 1996). Convincing experimental evidence to demonstrate that the function of NCAM in learning-associated synaptic plasticity can be modulated by PSA came from experiments where enzymatic removal of PSA resulted in decayed LTP in the hippocampus (Becker et al., 1996; Muller et al., 1996) and this was associated with an impaired acquisition and retention of spatial memory in the Morris water maze (Becker et al., 1996). Accordingly, impaired LTP of Schaffer collateral-CA1 synapses has been found in adult transgenic mice where PSA but not NCAM was absent in the hippocampal CA1 region due to deletion of polysialyltransferase ST8SiaIV (Eckhardt et al., 2000). This same mouse strain shows impaired learning in the water maze test (Markram et al., 2007a). Recent results suggests that the impact of PSA–NCAM in synaptic plasticity is not mediated by modulation of NCAM–NCAM homophilic interactions (Senkov et al., 2006). In these experiments, intraventricular administration of soluble PSA and PSA– NCAM-Fc but not NCAM-Fc fragments resulted in a strong impairment in contextual learning using the fear conditioning paradigm. Importantly, injection of PSA–NCAM but not NCAM into NCAM−/− mice resulted in a significant improvement of contextual learning as well as in a partial rescue of LTP. Altogether, while the exact mechanisms of actions remain to be determined, these data show an important active role for PSA–NCAM in the modulation of cognitive functions that is, at least partially, independent from the modulation of NCAMmediated cell adhesion. Synaptic plasticity in the amygdala, a brain area playing a decisive role in fear and anxiety, has been proposed to be an essential component in the generation of emotional memories (LeDoux, 2003). Almost all amygdaloid nuclei express PSA– NCAM in the adult rat (Nacher et al., 2002) and the functional role of PSA in the generation and extinction of fear memories has recently been explored using the auditory fear conditioning paradigm (Markram et al., 2007b). Similar to observations made in the hippocampal dentate gyrus following acquisition of hippocampus-related learning tasks, auditory fear conditioning enhanced PSA–NCAM expression in the amygdala. However, in contrast to hippocampus-dependent memory acquisition, enzymatic cleavage of the PSA moiety from the NCAM protein core by the enzyme Endo-N did not affect acquisition, consolidation or expression of remote fear memories. Rather, intra-amygdaloid cleavage of PSA facilitated fear extinction, suggesting that fear-conditioning induced upregulation of PSA–NCAM, while not necessary for the establishment of fear memories, participates in mechanisms precluding fear extinction. Multiple bidirectional interactions between the hippocampus, amygdala and the cerebral cortex are critical to complete processing of information relevant to learning and learningdependent modulation of NCAM polysialylation has also been explored in different cortical regions. Following the Morris water maze training, a two- to threefold transient timedependent increase in PSA content has been observed in the entorhinal cortex, raising the possibility that polysialylation of NCAM in corticohippocampal pathways might participate in complex molecular mechanisms underlying memory consolidation (O'Connell et al., 1997). Bidirectional pathways between the hippocampus and the septal nuclei also influence

memory processing (Everitt and Robbins, 1997) and hippocampus-dependent learning paradigms increase the number of polysialylated GABAergic neurons in the subtriangular septal zone of this region (Foley et al., 2003b), further arguing for a role of PSA–NCAM in memory consolidation in extrahippocampal structures. Finally, recent evidence indicates the involvement of PSA–NCAM on cognitive processing related to the medial prefrontal cortex (Markram et al., 2007a). This cortical structure plays a crucial role in the control of cognitive function both in rodents and humans (Uylings et al., 2003) and GABAergic neurons in this region have been reported to express PSA–NCAM (Varea et al., 2005). Transgenic mice, lacking the ST8SiaIV enzyme exhibit a nearly complete loss of PSA–NCAM in the adult prefrontal cortex and, thus, provide an important tool to evaluate the role of PSA on cognitive tasks relying on this region. In fact, reversal learning in the water maze, a learning task describing medial prefrontal cortex function, has been found to be seriously impaired in this mouse strain, suggesting the involvement of PSA–NCAM in behavioral and cognitive flexibility associated with the prefrontal cortex (Markram et al., 2007b). The environmental context exerts a crucial role on cognitive processing. Thus, it is important to decipher the cellular and molecular mechanisms underlying interactions between stress, cognitive-emotional state and memory. Chronic stress induces structural changes of neuronal architecture in the hippocampus, amygdala and the prefrontal cortex and is proposed to impair cognitive function (McEwen and Sapolsky, 1995). A 21-day-long chronic restraint stress procedure in rats has been reported to facilitate subsequent contextual fear conditioning and this is accompanied by reduced NCAM but increased PSA–NCAM expression (Sandi et al., 2001). However, increased polysialylation of NCAM during chronic stress seems to be only temporary, as the observed upregulation of PSA levels has been lost when the duration of stress exposure has been augmented up to 6 weeks (Pham et al., 2003). An overall reduction in PSA content has also been found in the amygdala following chronic restraint stress (Cordero et al., 2005), suggesting a potential mechanism for modulation of emotional states by chronic stress. The influence of excessive acute stress on hippocampusdependent memory acquisition may provide the pathological basis of memory disturbances, such as the posttraumatic stress disorder (Cahill, 1997) and trauma-induced amnesia (Richter-Levin, 1998). Using the hippocampus-dependent contextual fear conditioning paradigm (Kim and Fanselow, 1992), it has been demonstrated that behavioral responses depend on shock intensity. While weak (0.2 mA) and moderate (0.4 mA) shocks show positive correlation with the extent and duration of conditioned fear (Cordero et al., 1998), animals trained at high-shock intensities (1 mA) exhibit some of the characteristics seen with posttraumatic stress disorder (Cordero et al., 2002). Evaluating the shock intensity-dependent effect of the contextual fear conditioning paradigm on PSA– NCAM expression in the dentate gyrus (Sandi et al., 2003), it has been demonstrated that exposure to either low or moderate stimuli resulted in a temporary increase in the number of polysialylated neurons. In contrast, high shock intensity (1 mA) induced a significant decrease in the frequency of PSA–NCAM positive neurons at 12 h post-training

B RA I N RE SE A R CH RE V I EW S 56 ( 20 0 7 ) 1 0 1–1 1 8

time. Most importantly, the high shock-induced decrease in PSA content was correlated with impaired performance in the water maze while lower, non-traumatic, shock intensities facilitated learning (Sandi et al., 2003). Subsequent exposure of rats to predator stress (cat) following the water maze learning significantly increased the error rate during the memory test trial and this memory impairment was associated with reduced NCAM levels in the hippocampus and the prefrontal cortex (Sandi et al., 2005). Altogether, these observations strongly suggest the involvement of PSA–NCAM in the regulation of hippocampus-dependent stress-sensitive memory encoding systems that respond specifically to situations involving different stress levels.

6.

Conclusions

Based on the evidence reviewed above, NCAM/PSA–NCAM seem to dynamically regulate stability versus plasticity of neuronal networks and therefore could participate in underlying cognitive functions. The precise mechanism by which different NCAM isoforms may be involved in this process remains unclear. In vitro studies indicate that NCAM is associated with trans-Golgi organelles and the spectrin network and is involved in recruiting critical organelles and molecules to the synapse. This may serve to stabilize newly formed synapses and consolidate synaptic contacts at the late phase of LTP. PSA–NCAM is clearly expressed where adult plasticity occurs. These include circuits underlying learning and memory in the hippocampus, the medial prefrontal cortex and the enthorinal cortex and the neurogenic regions of the adult brain including the dentate gyrus and the subventricular olfactory bulb system (Arellano et al., 2002; Bonfanti, 2006; Kiss et al., 2001; Seki and Arai, 1991; Varea et al., 2005). It appears now well established that PSA–NCAM functions as a spacer. It weakens adhesion between opposing membranes allowing reorganization and movement. Most intriguingly, this spacer function may also allow signaling through growth factor receptors. One possibility is that PSA–NCAM-mediated interactions promote clustering and aggregation of receptor tyrosine kinases that would be compatible with dimerization and autophosphorylation (Fig. 2). The important consequence of this effect would be to promote a certain degree of receptor activation and phosphorylation even in the absence of ligands or growth factor. The NCAM-induced pre-clustering of receptor dimers could significantly facilitate receptor–ligand interactions and the rapidity and amplitude of signaling. Most importantly, this could provide a mechanism for localized activation of growth factor signaling and a more specific action on neurite outgrowth and synaptic plasticity. Weakening adhesion forces and switching to signaling mode by PSA– NCAM could play a permissive role during the initial phase of plasticity. Whether and how these permissive roles could affect instructive mechanisms of synaptic plasticity remain unknown. Recent evidence suggests that newly generated neurons might endow the adult brain with new levels of plasticity (Lledo et al., 2006). Interestingly, PSA–NCAM is tightly involved in regulating the biological properties of new neurons. For

113

example, the proper migration and survival of these cells appear to be dependent on PSA–NCAM (Cremer et al., 1994; Hu et al., 1996; Ono et al., 1994). The mechanism by which PSA– NCAM affects these processes is currently being investigated. Influencing p75 expression and signaling might play a fundamental role in these processes. It is intriguing that p75 receptors has been proposed to function both as a dependence receptor and a death receptor, depending on the cellular context (Bredesen et al., 2005). In the first case, the expression of p75 creates states of dependence on its ligands and activates death following the withdrawal of neurotrophic factors (Barrett and Bartlett, 1994; Rabizadeh et al., 1993). In the second, p75 may mediate the cellular response to a mismatched neurotrophin (e.g., exposure of a neuron-expressing TrkB and p75 to NGF, which binds TrkA and p75) through its function as a death receptor (Aloyz et al., 1998; CasacciaBonnefil et al., 1996; Frade et al., 1996). It is thus possible that by limiting p75 expression, PSA–NCAM may protect newborn neurons from being dependent on trophic support before integration into functional circuits. Neurons having reached their appropriate place and having established synaptic connections would be coupled to network activity that is critical for their long-term survival (Miwa and Storm, 2005; Rochefort et al., 2002). The progressive downregulation of PSA– NCAM and the increase in p75 expression during maturation would contribute to the elimination of non-integrated and/or misplaced cells. Numerous questions remain. For example, how the polysialylation state of NCAM is regulated during plasticity, such as acquisition and long-term memory? Does PSA–NCAM play a role in spine dynamics? Is there a possibility for local regulation of polysialylation of NCAM in the spine? How PSA–NCAM expression is correlated with stable versus labile spines? How and when PSA–NCAM is inserted into the cell membrane in a synapse that switches from firmly established contact to a labile one? Is the intracellular routing for NCAM versus PSA–NCAM different? Answering these questions represent the next challenges for the future. More importantly, with the recent association of PSA–NCAM with a number of psychiatric diseases, this information will be invaluable in the development of a therapeutic treatment for these disorders. REFERENCES

Aimone, J.B., et al., 2006. Potential role for adult neurogenesis in the encoding of time in new memories. Nat. Neurosci. 9, 723–727. Albach, C., et al., 2004. Identification of N-glycosylation sites of the murine neural cell adhesion molecule NCAM by MALDI-TOF and MALDI-FTICR mass spectrometry. Anal. Bioanal. Chem. 378, 1129–1135. Albright, T.D., et al., 2000. Neural science: a century of progress and the mysteries that remain. Cell 100, S1–S55 (Suppl.). Aloyz, R.S., et al., 1998. p53 is essential for developmental neuron death as regulated by the TrkA and p75 neurotrophin receptors. J. Cell Biol. 143, 1691–1703. Altman, J., 1962. Are new neurons formed in the brains of adult mammals? Science 135, 1127–1128. Alvarez-Buylla, A., et al., 2000. The subventricular zone: source of neuronal precursors for brain repair. Prog. Brain Res. 127, 1–11.

114

B RA I N R E SE A R CH RE V I EW S 56 ( 20 0 7 ) 1 0 1–1 1 8

Angata, K., Fukuda, M., 2003. Polysialyltransferases: major players in polysialic acid synthesis on the neural cell adhesion molecule. Biochimie 85, 195–206. Angata, K., et al., 2002. ST8Sia II and ST8Sia IV polysialyltransferases exhibit marked differences in utilizing various acceptors containing oligosialic acid and short polysialic acid. The basis for cooperative polysialylation by two enzymes. J. Biol. Chem. 277, 36808–36817. Angata, K., 2004. Sialyltransferase ST8Sia-II assembles a subset of polysialic acid that directs hippocampal axonal targeting and promotes fear behavior. J. Biol. Chem. 279, 32603–32613. Arellano, J.I., et al., 2002. PSA–NCAM immunoreactivity in chandelier cell axon terminals of the human temporal cortex. Cereb. Cortex 12, 617–624. Aubert, I., et al., 1998. Expression of L1 and PSA during sprouting and regeneration in the adult hippocampal formation. J. Comp. Neurol. 399, 1–19. Barbacid, M., 1994. The Trk family of neurotrophin receptors. J. Neurobiol. 25, 1386–1403. Barbeau, D., et al., 1995. Decreased expression of the embryonic form of the neural cell adhesion molecule in schizophrenic brains. Proc. Natl. Acad. Sci. U. S. A. 92, 2785–2789. Barberis, L., et al., 2000. Distinct roles of the adaptor protein Shc and focal adhesion kinase in integrin signaling to ERK. J. Biol. Chem. 275, 36532–36540. Barrett, G.L., et al., 1998. Rescue of dorsal root sensory neurons by nerve growth factor and neurotrophin-3, but not brain-derived neurotrophic factor or neurotrophin-4, is dependent on the level of the p75 neurotrophin receptor. Neuroscience 85, 1321–1328. Barrett, G.L., Bartlett, P.F., 1994. The p75 nerve growth factor receptor mediates survival or death depending on the stage of sensory neuron development. Proc. Natl. Acad. Sci. U. S. A. 91, 6501–6505. Becker, C.G., et al., 1996. The polysialic acid modification of the neural cell adhesion molecule is involved in spatial learning and hippocampal long-term potentiation. J. Neurosci. Res. 45, 143–152. Beggs, H.E., et al., 1997. NCAM140 interacts with the focal adhesion kinase p125(fak) and the SRC-related tyrosine kinase p59(fyn). J. Biol. Chem. 272, 8310–8319. Bliss, T.V., Collingridge, G.L., 1993. A synaptic model of memory: long-term potentiation in the hippocampus. Nature 361, 31–39. Bodrikov, V., et al., 2005. RPTPalpha is essential for NCAM-mediated p59fyn activation and neurite elongation. J. Cell Biol. 168, 127–139. Bonfanti, L., 2006. PSA–NCAM in mammalian structural plasticity and neurogenesis. Prog. Neurobiol. 80, 129–164. Bonfanti, L., et al., 1992. Mapping of the distribution of polysialylated neural cell adhesion molecule throughout the central nervous system of the adult rat: an immunohistochemical study. Neuroscience 49, 419–436. Bredesen, D.E., et al., 2005. Receptors that mediate cellular dependence. Cell Death Differ. 12, 1031–1043. Brocco, M.A., Frasch, A.C., 2006. Interfering polysialyltransferase ST8SiaII/STX mRNA inhibits neurite growth during early hippocampal development. FEBS Lett. 580, 4723–4726. Brummendorf, T., Rathjen, F.G., 1995. Cell adhesion molecules 1: immunoglobulin superfamily. Protein Profile 2, 963–1108. Bruses, J.L., et al., 2002. Polysialic acid and the formation of oculomotor synapses on chick ciliary neurons. J. Comp. Neurol. 446, 244–256. Bruses, J.L., Rutishauser, U., 2001. Roles, regulation, and mechanism of polysialic acid function during neural development. Biochimie 83, 635–643. Bukalo, O., et al., 2004. Conditional ablation of the neural cell adhesion molecule reduces precision of spatial learning, long-term potentiation, and depression in the CA1 subfield of mouse hippocampus. J. Neurosci. 24, 1565–1577.

Buonomano, D.V., Merzenich, M.M., 1998. Cortical plasticity: from synapses to maps. Annu. Rev. Neurosci. 21, 149–186. Burgess, A., Aubert, I., 2006. Polysialic acid limits choline acetyltransferase activity induced by brain-derived neurotrophic factor. J. Neurochem. 9, 797–806. Buttner, B., et al., 2003. The neural cell adhesion molecule is associated with major components of the cytoskeleton. Biochem. Biophys. Res. Commun. 310, 967–971. Cahill, L., 1997. The neurobiology of emotionally influenced memory. Implications for understanding traumatic memory. Ann. N. Y. Acad. Sci. 821, 238–246. Casaccia-Bonnefil, P., et al., 1996. Death of oligodendrocytes mediated by the interaction of nerve growth factor with its receptor p75. Nature 383, 716–719. Chao, M.V., 1994. The p75 neurotrophin receptor. J. Neurobiol. 25, 1373–1385. Chazal, G., et al., 2000. Consequences of neural cell adhesion molecule deficiency on cell migration in the rostral migratory stream of the mouse. J. Neurosci. 20, 1446–1457. Cole, G.J., Glaser, L., 1986. A heparin-binding domain from N-CAM is involved in neural cell-substratum adhesion. J. Cell Biol. 102, 403–412. Cordero, M.I., et al., 1998. Correlational relationship between shock intensity and corticosterone secretion on the establishment and subsequent expression of contextual fear conditioning. Behav. Neurosci. 112, 885–891. Cordero, M.I., et al., 2002. Glucocorticoid involvement in memory formation in a rat model for traumatic memory. Stress 5, 73–79. Cordero, M.I., et al., 2005. Chronic restraint stress down-regulates amygdaloid expression of polysialylated neural cell adhesion molecule. Neuroscience 133, 903–910. Costantini, C., et al., 2005. Characterization of the signaling pathway downstream p75 neurotrophin receptor involved in beta-amyloid peptide-dependent cell death. J. Mol. Neurosci. 25, 141–156. Cremer, H., et al., 1994. Inactivation of the N-CAM gene in mice results in size reduction of the olfactory bulb and deficits in spatial learning. Nature 367, 455–459. Cremer, H., et al., 1998. Long-term but not short-term plasticity at mossy fiber synapses is impaired in neural cell adhesion molecule-deficient mice. Proc. Natl. Acad. Sci. U. S. A. 95, 13242–13247. Daston, M.M., et al., 1996. Spatially restricted increase in polysialic acid enhances corticospinal axon branching related to target recognition and innervation. J. Neurosci. 16, 5488–5497. Dayer, A.G., et al., 2005. New GABAergic interneurons in the adult neocortex and striatum are generated from different precursors. J. Cell Biol. 168, 415–427. De Matteis, M.A., Morrow, J.S., 2000. Spectrin tethers and mesh in the biosynthetic pathway. J. Cell. Sci. 113 (Pt. 13), 2331–2343. Dityatev, A., et al., 2000. Synaptic strength as a function of post-versus presynaptic expression of the neural cell adhesion molecule NCAM. Neuron 26, 207–217. Dityatev, A., et al., 2004. Polysialylated neural cell adhesion molecule promotes remodeling and formation of hippocampal synapses. J. Neurosci. 24, 9372–9382. Dobrowsky, R.T., et al., 1994. Activation of the sphingomyelin cycle through the low-affinity neurotrophin receptor. Science 265, 1596–1599. Doetsch, F., 2003. A niche for adult neural stem cells. Curr. Opin. Genet. Dev. 13, 543–550. Doherty, P., Walsh, F.S., 1996. CAM-FGF receptor interactions: a model for axonal growth. Mol. Cell. Neurosci. 8, 99–111. Doyle, E., et al., 1992a. Hippocampal NCAM180 transiently increases sialylation during the acquisition and consolidation of a passive avoidance response in the adult rat. J. Neurosci. Res. 31, 513–523. Doyle, E., et al., 1992b. Intraventricular infusions of anti-neural cell adhesion molecules in a discrete posttraining period impair

B RA I N RE SE A R CH RE V I EW S 56 ( 20 0 7 ) 1 0 1–1 1 8

consolidation of a passive avoidance response in the rat. J. Neurochem. 59, 1570–1573. Durbec, P., et al., 1996. GDNF signalling through the Ret receptor tyrosine kinase. Nature 381, 789–793. Eckhardt, M., et al., 2000. Mice deficient in the polysialyltransferase ST8SiaIV/PST-1 allow discrimination of the roles of neural cell adhesion molecule protein and polysialic acid in neural development and synaptic plasticity. J. Neurosci. 20, 5234–5244. Edelman, G.M., 1986. Cell adhesion molecules in the regulation of animal form and tissue pattern. Annu. Rev. Cell Biol. 2, 81–116. Edelman, G.M., Cunningham, B.A., 1990. Place-dependent cell adhesion, process retraction, and spatial signaling in neural morphogenesis. Cold Spring Harbor Symp. Quant. Biol. 55, 303–318. Everitt, B.J., Robbins, T.W., 1997. Central cholinergic systems and cognition. Annu. Rev. Psychol. 48, 649–684. Finne, J., et al., 1983. Occurrence of alpha 2–8 linked polysialosyl units in a neural cell adhesion molecule. Biochem. Biophys. Res. Commun. 112, 482–487. Florence, S.L., et al., 1998. Large-scale sprouting of cortical connections after peripheral injury in adult macaque monkeys. Science 282, 1117–1121. Foley, A.G., et al., 2003a. Consolidation of memory for odour-reward association requires transient polysialylation of the neural cell adhesion molecule in the rat hippocampal dentate gyrus. J. Neurosci. Res. 74, 570–576. Foley, A.G., et al., 2003b. Distribution of polysialylated neural cell adhesion molecule in rat septal nuclei and septohippocampal pathway: transient increase of polysialylated interneurons in the subtriangular septal zone during memory consolidation. J. Neurosci. Res. 74, 807–817. Fox, G.B., et al., 1995. Memory consolidation induces a transient and time-dependent increase in the frequency of neural cell adhesion molecule polysialylated cells in the adult rat hippocampus. J. Neurochem. 65, 2796–2799. Frade, J.M., et al., 1996. Induction of cell death by endogenous nerve growth factor through its p75 receptor. Nature 383, 166–168. Frago, L.M., et al., 1998. Nerve growth factor and ceramides modulate cell death in the early developing inner ear. J. Cell. Sci. 111 (Pt 5), 549–556. Franz, C.K., et al., 2005. Polysialylated neural cell adhesion molecule is necessary for selective targeting of regenerating motor neurons. J. Neurosci. 25, 2081–2091. Garcia-Verdugo, J.M., et al., 1998. Architecture and cell types of the adult subventricular zone: in search of the stem cells. J. Neurobiol. 36, 234–248. Gascon, E., et al., 2005. Sequential activation of p75 and TrkB is involved in dendritic development of subventricular zone-derived neuronal progenitors in vitro. Eur. J. Neurosci. 21, 69–80. Gascon, E., et al., 2007. PSA–NCAM in postnatally generated immature neurons of the olfactory bulb: a crucial role in regulating p75 expression and cell survival. Development 134, 1181–1190. Gerlai, R., 2001. Behavioral tests of hippocampal function: simple paradigms complex problems. Behav. Brain Res. 125, 269–277. Geyer, H., et al., 2001. Core structures of polysialylated glycans present in neural cell adhesion molecule from newborn mouse brain. Eur. J. Biochem. 268, 6587–6599. Gould, E., Tanapat, P., 1999. Stress and hippocampal neurogenesis. Biol. Psychiatry 46, 1472–1479. Gould, E., 1999. Neurogenesis in the neocortex of adult primates. Science 286, 548–552. Hammond, M.S., et al., 2006. NCAM associated polysialic acid inhibits NR2B-containing NMDA receptors and prevents glutamate-induced cell death. J. Biol. Chem. 281, 34859–34869. Hartz, B.P., et al., 2003. A synthetic peptide ligand of NCAM affects

115

exploratory behavior and memory in rodents. Pharmacol. Biochem. Behav. 75, 861–867. He, Q., Meiri, K.F., 2002. Isolation and characterization of detergent-resistant microdomains responsive to NCAM-mediated signaling from growth cones. Mol. Cell. Neurosci. 19, 18–31. He, H.T., et al., 1986. Phosphatidylinositol is involved in the membrane attachment of NCAM-120, the smallest component of the neural cell adhesion molecule. EMBO J. 5, 2489–2494. Hebb, C.O., Konzett, H., 1949. The effect of certain analgesic drugs on synaptic transmission as observed in the perfused superior cervical ganglion of the cat. Q. J. Exp. Physiol. Cogn. Med. Sci. 35, 213–217. Hinkle, C.L., et al., 2006. Metalloprotease-induced ectodomain shedding of neural cell adhesion molecule (NCAM). J. Neurobiol. 66, 1378–1395. Hinsby, A.M., et al., 2004. Molecular mechanisms of NCAM function. Front. Biosci. 9, 2227–2244. Hirata, H., et al., 2001. Nerve growth factor signaling of p75 induces differentiation and ceramide-mediated apoptosis in Schwann cells cultured from degenerating nerves. Glia 36, 245–258. Hoffman, S., et al., 1982. Chemical characterization of a neural cell adhesion molecule purified from embryonic brain membranes. J. Biol. Chem. 257, 7720–7729. Hrynkow, S.H., et al., 1998. Multiple roles of neural cell adhesion molecule, neural cell adhesion molecule-polysialic acid, and L1 adhesion molecules during sensory innervation of the otic epithelium in vitro. Neuroscience 87, 423–437. Hu, H., et al., 1996. The role of polysialic acid in migration of olfactory bulb interneuron precursors in the subventricular zone. Neuron 16, 735–743. Huang, E.J., Reichardt, L.F., 2003. Trk receptors: roles in neuronal signal transduction. Annu. Rev. Biochem. 72, 609–642. Kasper, C., et al., 2000. Structural basis of cell–cell adhesion by NCAM. Nat. Struct. Biol. 7, 389–393. Kelleher III, R.J., et al., 2004. Translational regulatory mechanisms in persistent forms of synaptic plasticity. Neuron 44, 59–73. Kempermann, G., Gage, F.H., 2000. Neurogenesis in the adult hippocampus. Novartis Found. Symp. 231, 220–235 (discussion 235-41, 302-6). Kempermann, G., et al., 1997. More hippocampal neurons in adult mice living in an enriched environment. Nature 386, 493–495. Kilgard, M.P., Merzenich, M.M., 1998. Cortical map reorganization enabled by nucleus basalis activity. Science 279, 1714–1718. Kim, J.J., Fanselow, M.S., 1992. Modality-specific retrograde amnesia of fear. Science 256, 675–677. Kirkwood, A., et al., 1996. Experience-dependent modification of synaptic plasticity in visual cortex. Nature 381, 526–528. Kiryushko, D., et al., 2003. A synthetic peptide ligand of neural cell adhesion molecule (NCAM), C3d, promotes neuritogenesis and synaptogenesis and modulates presynaptic function in primary cultures of rat hippocampal neurons. J. Biol. Chem. 278, 12325–12334. Kiselyov, V.V., et al., 2003. Structural basis for a direct interaction between FGFR1 and NCAM and evidence for a regulatory role of ATP. Structure 11, 691–701. Kiselyov, V.V., et al., 2005. Structural biology of NCAM homophilic binding and activation of FGFR. J. Neurochem. 94, 1169–1179. Kiss, J.Z., Rougon, G., 1997. Cell biology of polysialic acid. Curr. Opin. Neurobiol. 7, 640–646. Kiss, J.Z., et al., 2001. The role of neural cell adhesion molecules in plasticity and repair. Brain Res. Brain Res. Rev. 36, 175–184. Kitazume-Kawaguchi, S., et al., 2001. Differential biosynthesis of polysialic or disialic acid structure by ST8Sia II and ST8Sia IV. J. Biol. Chem. 276, 15696–15703. Kojima, N., et al., 1995. Enzymatic activity of a developmentally regulated member of the sialyltransferase family (STX): evidence for alpha 2,8-sialyltransferase activity toward N-linked oligosaccharides. FEBS Lett. 360, 1–4.

116

B RA I N R E SE A R CH RE V I EW S 56 ( 20 0 7 ) 1 0 1–1 1 8

Kolkova, K., et al., 2000. Neural cell adhesion molecule-stimulated neurite outgrowth depends on activation of protein kinase C and the Ras-mitogen-activated protein kinase pathway. J. Neurosci. 20, 2238–2246. LeDoux, J., 2003. The emotional brain, fear, and the amygdala. Cell. Mol. Neurobiol. 23, 727–738. Leshchyns'ka, I., et al., 2003. Neural cell adhesion molecule (NCAM) association with PKCbeta2 via betaI spectrin is implicated in NCAM-mediated neurite outgrowth. J. Cell Biol. 161, 625–639. Lin, T.H., et al., 1997. Integrin-mediated activation of MAP kinase is independent of FAK: evidence for dual integrin signaling pathways in fibroblasts. J. Cell Biol. 136, 1385–1395. Livingston, B.D., et al., 1988. Extended polysialic acid chains (n greater than 55) in glycoproteins from human neuroblastoma cells. J. Biol. Chem. 263, 9443–9448. Lledo, P.M., et al., 2006. Adult neurogenesis and functional plasticity in neuronal circuits. Nat. Rev., Neurosci. 7, 179–193. Luthi, A., et al., 1994. Potentiation of a metabotropic glutamatergic response following NMDA receptor activation in rat hippocampus. Pflugers Arch. 427, 197–202. Luthl, A., et al., 1994. Hippocampal long-term potentiation and neural cell adhesion molecules L1 and NCAM. Nature 372, 777–779. Malenka, R.C., Bear, M.F., 2004. LTP and LTD: an embarrassment of riches. Neuron 44, 5–21. Markram, K., et al., 2007a. Selective learning and memory impairments in mice deficient for polysialylated NCAM in adulthood. Neuroscience 144, 788–796. Markram, K., et al., 2007b. Amygdala upregulation of NCAM polysialylation induced by auditory fear conditioning is not required for memory formation, but plays a role in fear extinction. Neurobiol. Learn. Mem. 87, 573–582. McEwen, B.S., Sapolsky, R.M., 1995. Stress and cognitive function. Curr. Opin. Neurobiol. 5, 205–216. Mendiratta, S.S., et al., 2005. Specific amino acids in the first fibronectin type III repeat of the neural cell adhesion molecule play a role in its recognition and polysialylation by the polysialyltransferase ST8Sia IV/PST. J. Biol. Chem. 280, 32340–32348. Mikkonen, M., et al., 1998. Remodeling of neuronal circuitries in human temporal lobe epilepsy: increased expression of highly polysialylated neural cell adhesion molecule in the hippocampus and the entorhinal cortex. Ann. Neurol. 44, 923–934. Mikkonen, M., et al., 1999. Hippocampal plasticity in Alzheimer's disease: changes in highly polysialylated NCAM immunoreactivity in the hippocampal formation. Eur. J. Neurosci. 11, 1754–1764. Milev, P., et al., 1995. Complex-type asparagine-linked oligosaccharides on phosphacan and protein-tyrosine phosphatase-zeta/beta mediate their binding to neural cell adhesion molecules and tenascin. J. Biol. Chem. 270, 24650–24653. Miller, F.D., Kaplan, D.R., 2001. Neurotrophin signalling pathways regulating neuronal apoptosis. Cell. Mol. Life Sci. 58, 1045–1053. Ming, G.L., Song, H., 2005. Adult neurogenesis in the mammalian central nervous system. Annu. Rev. Neurosci. 28, 223–250. Miwa, N., Storm, D.R., 2005. Odorant-induced activation of extracellular signal-regulated kinase/mitogen-activated protein kinase in the olfactory bulb promotes survival of newly formed granule cells. J. Neurosci. 25, 5404–5412. Monnier, P.P., et al., 2001. The polysialic acid moiety of the neural cell adhesion molecule is involved in intraretinal guidance of retinal ganglion cell axons. Dev. Biol. 229, 1–14. Morris, R.G., et al., 1982. Place navigation impaired in rats with hippocampal lesions. Nature 297, 681–683. Muhlenhoff, M., et al., 2001. The impact of N-glycosylation on the

functions of polysialyltransferases. J. Biol. Chem. 276, 34066–34073. Muller, D., et al., 1994. A role for polysialylated neural cell adhesion molecule in lesion-induced sprouting in hippocampal organotypic cultures. Neuroscience 61, 441–445. Muller, D., et al., 1996. PSA–NCAM is required for activity-induced synaptic plasticity. Neuron 17, 413–422. Muller, D., et al., 2000a. Brain-derived neurotrophic factor restores long-term potentiation in polysialic acid–neural cell adhesion molecule-deficient hippocampus. Proc. Natl. Acad. Sci. U. S. A. 97, 4315–4320. Muller, D., et al., 2000b. Spine changes associated with long-term potentiation. Hippocampus 10, 596–604. Murphy, K.J., Regan, C.M., 1999. Sequential training in separate paradigms impairs second task consolidation and learningassociated modulations of hippocampal NCAM polysialylation. Neurobiol. Learn. Mem. 72, 28–38. Murphy, K.J., et al., 1996. Repetitive and transient increases in hippocampal neural cell adhesion molecule polysialylation state following multitrial spatial training. J. Neurochem. 67, 1268–1274. Nacher, J., et al., 2002. Distribution of PSA–NCAM expression in the amygdala of the adult rat. Neuroscience 113, 479–484. Nakata, D., et al., 2006. Molecular basis for polysialylation: a novel polybasic polysialyltransferase domain (PSTD) of 32 amino acids unique to the alpha2,8-polysialyltransferases is essential for polysialylation. Glycoconj. J. 23, 423–436. Nakayama, J., et al., 1998. Polysialic acid, a unique glycan that is developmentally regulated by two polysialyltransferases, PST and STX, in the central nervous system: from biosynthesis to function. Pathol. Int. 48, 665–677. Nguyen, P.V., Kandel, E.R., 1996. A macromolecular synthesis-dependent late phase of long-term potentiation requiring cAMP in the medial perforant pathway of rat hippocampal slices. J. Neurosci. 16, 3189–3198. Nykjaer, A., et al., 2005. p75NTR—live or let die. Curr. Opin. Neurobiol. 15, 49–57. O'Connell, A.W., et al., 1997. Spatial learning activates neural cell adhesion molecule polysialylation in a corticohippocampal pathway within the medial temporal lobe. J. Neurochem. 68, 2538–2546. Ong, E., et al., 2002. Biosynthesis of HNK-1 glycans on O-linked oligosaccharides attached to the neural cell adhesion molecule (NCAM): the requirement for core 2 beta 1,6-Nacetylglucosaminyltransferase and the muscle-specific domain in NCAM. J. Biol. Chem. 277, 18182–18190. Ono, K., et al., 1994. N-CAM mutation inhibits tangential neuronal migration and is phenocopied by enzymatic removal of polysialic acid. Neuron 13, 595–609. Palmer, T.D., et al., 2000. Vascular niche for adult hippocampal neurogenesis. J. Comp. Neurol. 425, 479–494. Paratcha, G., et al., 2003. The neural cell adhesion molecule NCAM is an alternative signaling receptor for GDNF family ligands. Cell 113, 867–879. Petridis, A.K., et al., 2004. Polysialic acid regulates cell contact-dependent neuronal differentiation of progenitor cells from the subventricular zone. Dev. Dyn. 230, 675–684. Pham, K., et al., 2003. Repeated restraint stress suppresses neurogenesis and induces biphasic PSA–NCAM expression in the adult rat dentate gyrus. Eur. J. Neurosci. 17, 879–886. Pollerberg, G.E., et al., 1986. Differentiation state-dependent surface mobilities of two forms of the neural cell adhesion molecule. Nature 324, 462–465. Pollerberg, G.E., et al., 1987. The 180-kD component of the neural cell adhesion molecule N-CAM is involved in a cell–cell contacts and cytoskeleton-membrane interactions. Cell Tissue Res. 250, 227–236. Polo-Parada, L., et al., 2001. Alterations in transmission, vesicle

B RA I N RE SE A R CH RE V I EW S 56 ( 20 0 7 ) 1 0 1–1 1 8

dynamics, and transmitter release machinery at NCAM-deficient neuromuscular junctions. Neuron 32, 815–828. Purves, D., Andrews, T.J., 1997. The perception of transparent three-dimensional objects. Proc. Natl. Acad. Sci. U. S. A. 94, 6517–6522. Purves, D., et al., 1994. Categories of cortical structure. Prog. Brain Res. 102, 343–355. Rabizadeh, S., et al., 1993. Induction of apoptosis by the low-affinity NGF receptor. Science 261, 345–348. Retzler, C., et al., 1996. Analysis of neurocan structures interacting with the neural cell adhesion molecule N-CAM. J. Biol. Chem. 271, 27304–27310. Richter-Levin, G., 1998. Acute and long-term behavioral correlates of underwater trauma–potential relevance to stress and post-stress syndromes. Psychiatry Res. 79, 73–83. Rochefort, C., et al., 2002. Enriched odor exposure increases the number of newborn neurons in the adult olfactory bulb and improves odor memory. J. Neurosci. 22, 2679–2689. Ronn, L.C., et al., 1995. NCAM-antibodies modulate induction of long-term potentiation in rat hippocampal CA1. Brain Res. 677, 145–151. Ronn, L.C., et al., 1999. Identification of a neuritogenic ligand of the neural cell adhesion molecule using a combinatorial library of synthetic peptides. Nat. Biotechnol. 17, 1000–1005. Rothbard, J.B., et al., 1982. Differences in the carbohydrate structures of neural cell-adhesion molecules from adult and embryonic chicken brains. J. Biol. Chem. 257, 11064–11069. Rougon, G., 1993. Structure, metabolism and cell biology of polysialic acids. Eur. J. Cell Biol. 61, 197–207. Rousselot, P., et al., 1995. Embryonic (PSA) N-CAM reveals chains of migrating neuroblasts between the lateral ventricle and the olfactory bulb of adult mice. J. Comp. Neurol. 351, 51–61. Rutishauser, U., 1996. Polysialic acid and the regulation of cell interactions. Curr. Opin. Cell Biol. 8, 679–684. Rutishauser, U., Landmesser, L., 1996. Polysialic acid in the vertebrate nervous system: a promoter of plasticity in cell–cell interactions. Trends Neurosci. 19, 422–427. Rutishauser, U., et al., 1976. Mechanisms of adhesion among cells from neural tissues of the chick embryo. Proc. Natl. Acad. Sci. U. S. A. 73, 577–581. Rutishauser, U., et al., 1982. Binding properties of a cell adhesion molecule from neural tissue. Proc. Natl. Acad. Sci. U. S. A. 79, 685–689. Rutishauser, U., et al., 1988. The neural cell adhesion molecule (NCAM) as a regulator of cell–cell interactions. Science 240, 53–57. Saegusa, T., et al., 2004. Involvement of highly polysialylated neural cell adhesion molecule (PSA–NCAM)-positive granule cells in the amygdaloid-kindling-induced sprouting of a hippocampal mossy fiber trajectory. Neurosci. Res. 48, 185–194. Sandi, C., et al., 2001. Effects of chronic stress on contextual fear conditioning and the hippocampal expression of the neural cell adhesion molecule, its polysialylation, and L1. Neuroscience 102, 329–339. Sandi, C., et al., 2003. Modulation of hippocampal NCAM polysialylation and spatial memory consolidation by fear conditioning. Biol. Psychiatry 54, 599–607. Sandi, C., et al., 2005. Acute stress-induced impairment of spatial memory is associated with decreased expression of neural cell adhesion molecule in the hippocampus and prefrontal cortex. Biol. Psychiatry 57, 856–864. Schaller, M.D., 2001. Biochemical signals and biological responses elicited by the focal adhesion kinase. Biochim. Biophys. Acta 1540, 1–21. Schmid, R.S., et al., 1999. NCAM stimulates the Ras-MAPK pathway and CREB phosphorylation in neuronal cells. J. Neurobiol. 38, 542–558. Seidenfaden, R., et al., 2003. Polysialic acid directs tumor cell

117

growth by controlling heterophilic neural cell adhesion molecule interactions. Mol. Cell. Biol. 23, 5908–5918. Seidenfaden, R., et al., 2006. Glial conversion of SVZ-derived committed neuronal precursors after ectopic grafting into the adult brain. Mol. Cell. Neurosci. 32, 187–198. Seki, T., Arai, Y., 1991. Expression of highly polysialylated NCAM in the neocortex and piriform cortex of the developing and the adult rat. Anat. Embryol. (Berl) 184, 395–401. Seki, T., Rutishauser, U., 1998. Removal of polysialic acid–neural cell adhesion molecule induces aberrant mossy fiber innervation and ectopic synaptogenesis in the hippocampus. J. Neurosci. 18, 3757–3766. Senkov, O., et al., 2006. Polysialylated neural cell adhesion molecule is involved in induction of long-term potentiation and memory acquisition and consolidation in a fear-conditioning paradigm. J. Neurosci. 26, 10888–109898. Singer, W., 1986. The brain as a self-organizing system. Eur. Arch. Psychiatry Neurol. Sci. 236, 4–9. Soroka, V., et al., 2003. Structure and interactions of NCAM Ig1-2-3 suggest a novel zipper mechanism for homophilic adhesion. Structure 11, 1291–1301. Squire, L.R., et al., 1993. The structure and organization of memory. Annu. Rev. Psychol. 44, 453–495. Storms, S.D., et al., 1996. NCAM-mediated adhesion of transfected cells to agrin. Cell Adhes. Commun. 3, 497–509. Sytnyk, V., et al., 2002. Neural cell adhesion molecule promotes accumulation of TGN organelles at sites of neuron-to-neuron contacts. J. Cell Biol. 159, 649–661. Sytnyk, V., et al., 2004. Trans-Golgi network delivery of synaptic proteins in synaptogenesis. J. Cell. Sci. 117, 381–388. Sytnyk, V., et al., 2006. NCAM promotes assembly and activity-dependent remodeling of the postsynaptic signaling complex. J. Cell Biol. 174, 1071–1085. Theodosis, D.T., et al., 2004. Neuronal, glial and synaptic remodeling in the adult hypothalamus: functional consequences and role of cell surface and extracellular matrix adhesion molecules. Neurochem. Int. 45, 491–501. Tomasiewicz, H., et al., 1993. Genetic deletion of a neural cell adhesion molecule variant (N-CAM-180) produces distinct defects in the central nervous system. Neuron 11, 1163–1174. Troncoso, E., et al., 2004. Recovery of evoked potentials, metabolic activity and behavior in a mouse model of somatosensory cortex lesion: role of the neural cell adhesion molecule (NCAM). Cereb. Cortex 14, 332–341. Trupp, M., 1999. Ret-dependent and -independent mechanisms of glial cell line-derived neurotrophic factor signaling in neuronal cells. J. Biol. Chem. 274, 20885–20894. Tsuji, S., 1996. Molecular cloning and functional analysis of sialyltransferases. J. Biochem. (Tokyo) 120, 1–13. Uylings, H.B., et al., 2003. Do rats have a prefrontal cortex? Behav. Brain Res. 146, 3–17. Vaithianathan, T., et al., 2004. Neural cell adhesion molecule-associated polysialic acid potentiates alpha-amino3-hydroxy-5-methylisoxazole-4-propionic acid receptor currents. J. Biol. Chem. 279, 47975–47984. Van der Borght, K., et al., 2005. Morris water maze learning in two rat strains increases the expression of the polysialylated form of the neural cell adhesion molecule in the dentate gyrus but has no effect on hippocampal neurogenesis. Behav. Neurosci. 119, 926–932. van Praag, H., et al., 1999. Running enhances neurogenesis, learning, and long-term potentiation in mice. Proc. Natl. Acad. Sci. U. S. A. 96, 13427–13431. Varea, E., 2005. v expression in the rat medial prefrontal cortex. Neuroscience 136, 435–443. Varki, A., 1993. Biological roles of oligosaccharides: all of the theories are correct. Glycobiology 3, 97–130. Venero, C., et al., 2006. Hippocampal up-regulation of NCAM

118

B RA I N R E SE A R CH RE V I EW S 56 ( 20 0 7 ) 1 0 1–1 1 8

expression and polysialylation plays a key role on spatial memory. Eur. J. Neurosci. 23, 1585–1595. von Der Ohe, M., et al., 2002. Localization and characterization of polysialic acid-containing N-linked glycans from bovine NCAM. Glycobiology 12, 47–63. Vutskits, L., et al., 2001. PSA–NCAM modulates BDNF-dependent survival and differentiation of cortical neurons. Eur. J. Neurosci. 13, 1391–1402. Vutskits, L., et al., 2003. Removal of PSA from NCAM affects the survival of magnocellular vasopressin- and oxytocinproducing neurons in organotypic cultures of the paraventricular nucleus. Eur. J. Neurosci. 17, 2119–2126. Vutskits, L., et al., 2006. The polysialylated neural cell adhesion molecule promotes neurogenesis in vitro. Neurochem. Res. 31, 215–225. Walmod, P.S., et al., 2004. Zippers make signals: NCAM-mediated molecular interactions and signal transduction. Neurochem. Res. 29, 2015–2035. Walsh, F.S., et al., 1989. Tissue specific O-linked glycosylation of the neural cell adhesion molecule (N-CAM). Development 105, 803–811. Wang, C., et al., 1996. Functional N-methyl-D-aspartate receptors in O-2A glial precursor cells: a critical role in regulating polysialic acid–neural cell adhesion molecule expression and cell migration. J. Cell Biol. 135, 1565–1581. Wang, K.C., et al., 2002. P75 interacts with the Nogo receptor as a co-receptor for Nogo, MAG and OMgp. Nature 420, 74–78.

Weber, M., et al., 2006. Increased polysialic acid neural cell adhesion molecule expression in human hippocampus of heroin addicts. Neuroscience 138, 1215–1223. Wechsler, A., Teichberg, V.I., 1998. Brain spectrin binding to the NMDA receptor is regulated by phosphorylation, calcium and calmodulin. EMBO J. 17, 3931–3939. Weinhold, B., et al., 2005. Genetic ablation of polysialic acid causes severe neurodevelopmental defects rescued by deletion of the neural cell adhesion molecule. J. Biol. Chem. 280, 42971–42977. Williams, E.J., et al., 1994. Tyrosine kinase inhibitors can differentially inhibit integrin-dependent and CAM-stimulated neurite outgrowth. J. Cell Biol. 124, 1029–1037. Williams, E.J., et al., 2003. The FGF receptor uses the endocannabinoid signaling system to couple to an axonal growth response. J. Cell Biol. 160, 481–486. Yamamoto, N., et al., 2000. Inhibitory mechanism by polysialic acid for lamina-specific branch formation of thalamocortical axons. J. Neurosci. 20, 9145–9151. Yuste, R., Bonhoeffer, T., 2001. Morphological changes in dendritic spines associated with long-term synaptic plasticity. Annu. Rev. Neurosci. 24, 1071–1089. Zhang, L., et al., 2002. Role of Raf-1 and FAK in cell density-dependent regulation of integrin-dependent activation of MAP kinase. Carcinogenesis 23, 1251–1258. Zhang, H., et al., 2004. or the polysialic acid–neural cell adhesion molecule in PDGF-induced chemotaxis of oligodendrocyte precursor cells. J. Cell. Sci. 117, 93–103.