- Email: [email protected]
Neuropsin—A possible modulator of synaptic plasticity
Journal of Chemical Neuroanatomy 42 (2011) 24–29
Contents lists available at ScienceDirect
Journal of Chemical Neuroanatomy journal homepage: www.elsevier.com/locate/jchemneu
Review
Neuropsin—A possible modulator of synaptic plasticity Sadao Shiosaka a,b,*, Yasuyuki Ishikawa a a b
Laboratory of Functional Neuroscience, Nara Institute of Science and Technology, 8916-5, Takayama, Ikoma, Nara 630-0192, Japan The CREST program from the Ministry of Education, Culture, Sports, Science, and Technology, Japan
A R T I C L E I N F O
A B S T R A C T
Article history: Received 2 December 2010 Received in revised form 30 May 2011 Accepted 30 May 2011 Available online 6 June 2011
Accumulating evidence has suggested pivotal roles for neural proteases in development, maturation, aging, and cognitive functions. Among such proteases, neuropsin, a kallikrein gene-related (KLK) endoprotease, appears to have a significant plasticity function that has been analyzed primarily in the hippocampal Schaffer-collateral pathway. In this article, after reviewing the general features of neuropsin, its role in Schaffer-collateral synaptic plasticity is discussed in some detail. Enzymatically active neuropsin is necessary to establish the early phase of long-term potentiation (LTP). This type of LTP, which can be elicited by rather weak tetanic stimulation, is significant in synaptic late association between two independent hippocampal synapses. Neuropsin deficiency completely impaired the early phase of LTP, leading to the absence of late associativity. Associations between early and persistent-LTP synapses may be related to mammalian working memory and consequently integration in learning and memory. ß 2011 Elsevier B.V. All rights reserved.
Keywords: KLK8 LTP Serine protease Extracellular matrix Cell adhesion molecules Synaptic tagging
Contents 1. 2. 3. 4. 5. 6. 7. 8.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Expression of KLK8 in the brain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Evolution of KLK8. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Protein structure and zymogen activation of neuropsin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Potential substrates and receptors of neuropsin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Involvement of neuropsin on the early phase of synaptic plasticity, late associativity, and behavioral Little overlap in plasticity roles among neural proteases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Perspectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Introduction The concept that macromolecular cleavage or shedding in the synaptic cleft mediates intracellular signals involved in synaptic functions has become increasing familiar in the field of neuroscience. Reverse-transcription polymerase chain reaction for mouse hippocampal mRNAs using primers designed based on the consensus catalytic domain of secretory serine proteases screened out several protease genes including kallikrein-related
* Corresponding author at: Laboratory of Functional Neuroscience, Nara Institute of Science and Technology (NAIST), 8916-5, Takayama, Ikoma, Nara 630-0192, Japan. Tel.: +81 74372 5410; fax: +81 74372 5419. E-mail address: [email protected] (S. Shiosaka). 0891-0618/$ – see front matter ß 2011 Elsevier B.V. All rights reserved. doi:10.1016/j.jchemneu.2011.05.014
........ ........ ........ ........ ........ memory . ........ ........ ........
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
24 25 25 26 26 27 27 28 28
endopeptidase gene1 (KLK) 8, encoding neuropsin (alternative terminology: TADG-14, bsp1, or ovasin); KLK6, encoding neurosin (alternative terminology: zyme or protease M); and tissue plasminogen activator (tPA)2 (Chen et al., 1995). Currently, accumulating evidence supports pivotal roles of
1 The gene terminology was later unified according to the family of human kallikrein-related peptidase (KLK) genes. In humans, unlike in rodents, 15 homologous KLK genes were aligned in the centromere-distal direction on chromosome 19q13.3-4, regardless of some confusion in their ordering (Yousef and Diamandis, 2003). For an overview of KLK family proteases, current review articles written by Lundwall and Brattsand (2008), and Clements (2008) should be referred to. 2 The significance of tPA in neural plasticity has been described elsewhere: (Qian et al., 1993; Baranes et al., 1998; Yoshida and Shiosaka, 1999; Pawlak et al., 2005).
S. Shiosaka, Y. Ishikawa / Journal of Chemical Neuroanatomy 42 (2011) 24–29
Type1 preproneuropsin SS2
S
SS1
Q
SS6
Ser-protease
T1
H118
Type2 preproneuropsin
D165
S257
Type2 proneuropsin SS2
S
Type1 proneuropsin neuropsin SS5 SS3 SS4
25
T2
SS5 SS3 SS4
SS1
SS6
Ser-protease
Q H118
D165
S257
Fig. 1. Domain structures of human Type 1 and 2 preproneuropsin. H118,D165,S257, amino acids of catalytic triad; S, signal sequence; ser-protease, serine protease domain; SS16, disulfide bond 1-6; T1, type 1 specific domain (GHSRA); T2, type 2 specific domain (CGSLDLLTKLYAENLPCVHLNPQWPSQPSHCPRGWRSNPLPPAAGHSRA); Q, QEDK activity masking peptide.
these neural proteases not only in development, maturation, and aging, but also in higher nervous functions such as cognition. Here, we review the general features of neuropsin and discuss its possible roles in synaptic plasticity, particularly in the hippocampal region. 2. Expression of KLK8 in the brain Under non-pathological conditions, KLK8 (neuropsin gene) is localized mainly to the principal neurons of the limbic brain. In situ hybridization histochemistry for KLK8 demonstrated dense signals in pyramidal neurons of the hippocampal CA1–3 subfields and magnocellular neurons of the lateral/basolateral amygdaloid nucleus (Chen et al., 1995). Significant signals were also observed in pyramidal neurons of the cerebral cortex including prefrontal, cingulate and entorhinal regions. Initial investigation into the physiological effects of neuropsin focused on the main function of the hippocampus, neural plasticity, because KLK8 was observed at the highest density in the pyramidal neurons that compose the main hippocampal neural networks and was clearly regulated in a neural activity-dependent manner (Chen et al., 1995; Okabe et al., 1996). A variety of transcriptional controls through both physiological and nonphysiological activity, such as long-term potentiation (LTP), chemically induced plasticity, kindling epileptogenesis, and experimental encephalitis, have been shown to positively regulate KLK8 gene expression (Yoshida and Shiosaka, 1999). Later experiments have shown that KLK8 is not the neuron-specific gene we initially assumed. In addition to the neural expression described above, KLK8 mRNA was found to be widely expressed in stratified squamous epithelium, lung, thymus, pituitary (Chen et al., 1998), and uterus (Matsumoto-Miyai et al., 2002), as well as in pathological tissues (Kuwae et al., 2002; Terayama et al., 2005). 3. Evolution of KLK8 KLK8 is a member of the KLK multigene family, which is located on a single chromosome, 7B2 in mouse and 19q13.4 in human. Although basic proteolytic enzymes emerged very early in the most primitive organisms, the evolution of KLK-family genes, including KLK8, is a recent phenomenon. In silico investigation of the KLK family indicated that there was no KLK in bird (chicken) or amphibian (African clawed frog) species, but orthologues of KLK5– 15 were found in marsupial species (opossum) (Elliott et al., 2006).
Almost family member genes (KLK1–15) presumably completed in primitive mammals and are thereafter conserved in genomes of mouse, rat, dog, pig, macaque, chimpanzee, orangutan, gorilla, and human. Additionally, some species (i.e., mouse and rat) have an expanded family of genes with genetic diversity (Elliott et al., 2006; Lundwall and Brattsand, 2008). Each member of the multigene family may have evolved through sequence exchanges from a common ancestor and a conserved activity domain, which demonstrated similar trypsin-like catalytic activity toward peptide bonds (Arg-X and Lys-X) (Debela et al., 2006). Although they share similar peptidolytic activity to cleave chromogenic synthetic peptides (Merops peptidase database: http://merops.sanger.ac.uk/), each KLK has developed dissimilar substrate specificity for macromolecules and different tissue-specific expression patterns, and therefore may have discrete physiological functions. KLK8 also emerged in an ancestor of marsupial species and, thereafter, may have evolved independently from other KLKs. Lower mammals, including the mouse, rat, dog and pig, have only one orthologue (type 1 KLK8) in the genome. The limbic-specific expression of KLK8 is well conserved from rodent to human3 under non-pathological conditions. Comparative neuroanatomy has indicated that a primitive cortex and hippocampus emerged in the common ancestor of marsupials and monotremes, and, thereafter, limbic and cortical regions underwent progressive encephalization in mammals. It is intriguing how and why three discrete phenomena, i.e., the emergence of (1) KLK8, (2) target substrate molecules, and (3) complex neural networks in the limbic brain, coevolved in parallel to produce unique mammalian neural plasticity. In addition to type 1 KLK8, Mitsui et al. (1999) identified type 2 KLK8, a splicing variant of type 1, in the human brain. Phylogenic studies revealed that type 2 KLK8 was undetectable in mammalian brains from rodents to nonhuman primates (Li et al., 2004; Lu et al., 2007). In humans, type 2 KLK8 was dominantly expressed over type 1 in adult prefrontal cortical areas as well as in the hippocampus (Lu et al., 2007). However, type 1 and 2 KLK8 potentially produce the same zymogen (proneuropsin) and active enzyme (neuropsin) by the removal of the signal peptide and activity-masking peptide, respectively, and seem to result in a single form of neuropsin (Kishi et al., 1999; Oka et al., 2002) (Fig. 1). Since the effects of neuropsin on early phase LTP, which will be 3 Unpublished data from in situ hybridization histochemistry using postmortem human brain.
26
S. Shiosaka, Y. Ishikawa / Journal of Chemical Neuroanatomy 42 (2011) 24–29
discussed in the following section, depend on its enzymatic activity, detecting a special role for type 2-derived neuropsin in regulating the magnitude of synaptic potentiation may be difficult. The long form of proneuropsin (type 2 proneuropsin) may contribute to another unknown function such as the efficiency of synthesis and/or secretion of the zymogen. A human-specific point mutation triggers the change in splicing pattern, leading to the origin of the novel splice form in the human brain. Lu et al. (2007) suggested the critical involvement of type 2 KLK8 in the development of cognitive function during hominization from nonhuman primate to human. Intriguingly, type 2 KLK8 mRNA was not observed in chimpanzee or orangutan brain in spite of its intact open reading frame (Li et al., 2004). Thus, while it remains a hypothetical consideration, type 2 proneuropsin in the human limbic brain (including hippocampus and prefrontal areas) may contribute to functions related to human-specific (or highly developed) cognitive behavior. This hypothesis may be partially supported by the current analysis of single-nucleotide polymorphisms (SNPs) in the human genome. Izumi et al. (2008) conducted polymorphism screening for the entire human KLK8 and compared allelic and genotypic distributions between SNPs in patients with bipolar disorder and normal controls. They reported a significant allelic association between several SNPs and bipolar disorder. Carrying the risk allele for bipolar disorder was significantly associated with lower verbal IQ score, but, interestingly, no change in performance IQ (Izumi et al., 2008). Thus, genetic variation of the KLK8 gene may be involved in the molecular mechanisms of psychiatric disorders and some aspects of memory and intelligence. 4. Protein structure and zymogen activation of neuropsin All proteases in the KLK family are homologous with (chymo)trypsin and have well-conserved amino acid sequences and structures, particularly in the catalytic domain (Kishi et al., 1999; Bernett et al., 2002; Debela et al., 2006). The crystal structure of (type 1) neuropsin contains a serine protease fold that exhibits chimeric features of trypsin and g-NGF, both of which are part of the S1 family (clan SA) of serine proteases according to the Melops classification (Kishi et al., 1999; Bernett et al., 2002). Six surface loop structures of the protein were found to be essential for the generation of specific enzymatic activity and/or secretion of the enzyme via a regulated secretory pathway (Oka et al., 2002). In addition to the transcriptional regulation of KLK8 described above, increase in the amidolytic activity of neuropsin is regulated by neural activity, with activational processing of the zymogen, proneuropsin. Inactive extracellular proneuropsin, which is produced and secreted by signal peptide removal, was found to undergo activational processing to generate the mature active neuropsin by further removal of the N-terminus activity-masking peptide (QGSK and QEDK in mouse and human, respectively) (Shimizu et al., 1998). The neuropsin-activating enzyme that can remove QXXK has not yet been identified. Plasmin and matrix metalloprotease (MMP)-9 are potent activators from the perspective of substrate specificity, localization to neural tissue, and dependency on neural activity. Our preliminary experiments indicate that plasmin can activate the proneuropsin into neuropsin in vitro (unpublished data). However, further work is necessary to determine potential activators of proneuropsin when LTP-inducible neural activity is transmitted into postsynaptic machinery. The blockade of neuropsin activation critically stopped early phase LTP without any effect on basal synaptic transmission, and LTP-inducing tetanus was shown to activate proneuropsin to the active protease briefly after tetanic stimulation (Komai et al., 2000; Tamura et al., 2006,2008). These data can be interpreted as a sequential signaling cascade following four steps. LTP-inducing
stimulation leads to the activation of N-methyl D-aspartic acid (NMDA) receptor-linked signaling (1), which is followed by transient activation of enzymatically non-active proneuropsin into active neuropsin (2) (Matsumoto-Miyai et al., 2003). This neuropsin activity can cleave substrates to modulate pre- and postsynaptic elements (3) (Matsumoto-Miyai et al., 2003; Attwood et al., 2011). The process finally mediates a-amino-3-hydroxyl-5methyl-4-isoxazole-propionate (AMPA) receptors, which receive LTP-dependent modulation (4) (Tamura et al., 2006). In fact, recombinant active neuropsin itself dose-dependently elicited increased LTP-specific (Ser-831) phosphorylation of the type 1 subunit (GluR1) of the AMPA receptor (Tamura et al., 2006). Similarly, high doses of recombinant neuropsin elicited long-term depression (LTD)-specific (Ser-845) phosphorylation on GluR1. The GluR1 subunit is known to be phosphorylated by Ca2+/calmodulindependent kinase II (CAMKII) or protein kinase C (PKC) at Ser-831, and protein kinase A (PKA) at Ser-845, which are established markers of synaptic plasticity (Soderling and Derkach, 2000). Therefore, neuropsin may have an effect on the same intracellular signaling steps as electric tetanic stimulation and thus mimic such plasticity signaling through the cleavage of appropriate target molecules. 5. Potential substrates and receptors of neuropsin Since consensus sequences cleaved by neuropsin are not yet fully established, screening target macromolecules on the basis of such substrate specificity is difficult. However, some extracellular domains of transmembrane and extracellular matrix proteins have been identified by in vitro assays using randomly selected native or recombinant proteins. Generally, specific cleavage sites are present in or around the fibronectin domain of fibronectin (Shimizu et al., 1998), L1-cell adhesion molecule (L1cam) (Matsumoto-Miyai et al., 2003; Nakamura et al., 2006), and EPH receptor B2 (EphB2; the receptor tyrosine kinase) (Attwood et al., 2011) (Fig. 2). Neural excitation in the hippocampus makes neuropsin to cleave extracellular domain of L1cam. Increased neural activity triggers the rapid activation (a few minutes after stimulation) of proneuropsin in an NMDA receptor-dependent manner. The initiation of enzyme activity coincides with phosphorylation by CAMKII, PKA and PKC within the early LTP period (Soderling and Derkach, 2000; Matsumoto-Miyai et al., 2003). However, unlike these kinases with prolonged activity, neuropsin activity quickly decreases to baseline level after a few more minutes. Because activation is so transient, neuropsin must have a prompt substrate cleavage mechanism that can reach completion during the brief activation period. The activated neuropsin immediately cleaved substrates to release the extracellular domain and thereby to induce Schaffer-collateral LTP in an NMDA receptor-dependent manner (Matsumoto-Miyai et al., 2003). Another recent study investigated cleavage of EphB2 by neuropsin in the lateral amygdaloid nucleus. Increased anxietylike response (cued fear conditioning and elevated plus maze) was observed in neuropsin-deficient mice. Attwood et al. (2011) have shown that neuropsin is involved in stress-related plasticity in the amygdala by the cleavage of EphB2 during stress and the reduction of EphB2-NMDA binding. This event results in the facilitation of NMDA-receptor-dependent gene expression to regulate synaptic regulation and, thus, to control stress-induced anxiety in the amygdala. Neuropsin-driven synaptic modification via synaptic or peri-synaptic proteolysis may facilitate the dynamic interaction of intercellular signaling components during the early period of LTP and in stress-related behavior. Some kallikrein-related peptidases (5 and 14) can induce protease-activated receptor (PAR) signaling in the skin and brain (Stefansson et al., 2008; Vandell et al., 2008). However, there is no evidence to indicate that neuropsin is involved in PAR-related
S. Shiosaka, Y. Ishikawa / Journal of Chemical Neuroanatomy 42 (2011) 24–29
27
Fig. 2. Involvement of neural proteases in synaptic plasticity. Extracellular secretory proteases cleave various CAMs and ECM proteins (solid arrows) and are involved in intracellular signaling (broken arrows) to execute complex synaptic functions (bold letters). Abbreviations: AMPAR, a amino-3-hydroxyl-5-methyl-4-isoxazole-propionate receptor; proBDNF, pro-brain-derived neurotrophic factor; CaMKII, calcium/calmodulin-dependent protein kinase II; early LTP, early-phase of long-term potentiation; ECMs, extracellular matrices; EphB2, EPH receptor B2; L1cam, L1 cell adhesion molecule; late LTP, late-phase of long-term potentiation; LRP, low-density lipoprotein-related receptor; MMP9, matrix metalloprotease 9; NMDAR, N-methyl D-aspartic acid receptor; PKC, protein kinase C; PSD95, postsynaptic density protein 95; tPA, tissue plasminogen activator.
signaling. Neuropsin recombinant protein had no thrombin-like platelet coagulation activity when applied to platelets (Shimizu et al., 1998). Moreover, cells stably expressing the PAR-2 gene did not respond to intracellular Ca2+ mobilization by application of neuropsin (Stefansson et al., 2008). Therefore, neuropsin appears to function via system(s) that are discrete from PAR signaling. 6. Involvement of neuropsin on the early phase of synaptic plasticity, late associativity, and behavioral memory Hippocampal early phase LTP elicited by a weak (one 100-Hz) tetanic stimulus normally fades within 90 min. This form of LTP is independent of protein synthesis. In contrast, late-phase LTP elicited by a strong (four 100-Hz) stimulus lasts >180 min and requires new protein synthesis to persist, thus representing protein synthesisdependent LTP. These two temporal phases of LTP occur independently to establish hyperefficacy in synaptic transmission and are regulated by different signaling systems (Krug et al., 1984). Neuropsin deficiency or infusion of a neuropsin-specific inhibitor or anti-neuropsin monoclonal antibody strongly impaired early phase LTP induced by a single tetanus, but not late-phase LTP induced by a stronger stimulus (four tetani). Thus, the plasticity effects of neuropsin are exclusively significant in early phase LTP and not significant in late-phase LTP (Tamura et al., 2006; Ishikawa et al., 2008). Such remarkable participation by neuropsin in early phase LTP led to its examination in a late associativity protocol based on the theory of synaptic tagging (Frey and Morris, 1997). Neuropsin-dependent early phase LTP can be converted into persistent LTP by association with a synapse at which late-phase LTP is preestablished (Ishikawa et al., 2008, in press). This phenomenon is explained by the hypothetical concept of placing a mark (tag) on sites of weak stimulation at a particular synapse (Frey and Morris, 1997). Because local protein synthesis is not observed in weakly stimulated synapses, the proteins necessary for persistence are likely transported from other transcription and translation sites to tagged synaptic areas (Frey and Morris, 1997). Here, a weakly stimulated synapse can receive and capture newly synthesized synaptic proteins. Through this capturing of synthesized proteins, a weakly stimulated synapse is converted into a persistent LTP synapse (late associativity) without the stimulation required to induce late-phase
LTP. Synaptic tagging and late associativity may be particularly important in non-stressful associative memory and, to some significant degree, is considered neuropsin-dependent (Ishikawa et al., 2008). Since neuropsin is localized to the prefrontal, cingulate, and entorhinal cortices and amygdaloid complex in addition to the hippocampus, it may be reasonable to hypothesize that neuropsin also acts on synaptic association in these brain regions. The early plasticity effect of neuropsin was also apparent in behavioral tests using neuropsin-deficient mice. Spontaneous alternation in the Y-maze is a non-stressful behavioral task regarded as a spatial working memory test. Neuropsin-deficient mice exhibited a lower alternation ratio of path selection than wild-type mice. In the Morris water maze, the mice exhibited mildly impaired learning acquisition. Since stronger stimuli preferentially elicit late-phase LTP, it is reasonable that the water maze task, which is relatively stressful for mice, induced rather mild impairment in knockout mice. Neuropsin deficiency also led to enhanced cued memory in fear conditioning but had no effect on contextual fear memory (Horii et al., 2008). The absence of impairment to context-dependent fear conditioning (hippocampus-dependent memory, tested in the Barnes maze) is consistent with the dependence of contextual memory on late-phase LTP. 7. Little overlap in plasticity roles among neural proteases Although the cleavage/shedding of extracellular proteins by neural proteases has not yet been fully clarified, results obtained to date based on substrate specificities and differences in physiological responses indicate that each protease seems to have separate, nonredundant functions in plasticity. Neural proteases are known to be involved in LTP through the potential cleavage/shedding of cell adhesion molecules (CAMs) and extracellular matrix (ECM) proteins (Qian et al., 1993; Momota et al., 1998; Komai et al., 2000; Nakagami et al., 2000; Nagy et al., 2006; Bozdagi et al., 2007; Dityatev et al., 2010; Malinverno et al., 2010) (Table 1).) Antibodies against CAMs and inhibitors of the substrate binding domain of the neural proteases are also recognized to block LTP (Luthl et al., 1994; Schuster et al., 1998). Several proteases other than neuropsin are also known to be involved in neural plasticity. tPA is a well-characterized protease related to synaptic plasticity. A null mutation of the tPA gene in mice
S. Shiosaka, Y. Ishikawa / Journal of Chemical Neuroanatomy 42 (2011) 24–29
28
Table 1 Molecules in the synaptic cleft involved in early or late LTP. Category Extracellular protease
Cell adhesion or matrix protein
Molecule
LTP type involved in
Involvement in spine morphology change
Type of memory tasks involved in
References
Neuropsin
Early LTP b1integrin-mediated
Smaller synapses increase in L1cam orphan bouton
Hirata et al. (2001), Davies et al. (2001), Tamura et al. (2006), Horii et al. (2008)
Tissue plasminogen activator
Late LTP
Formation of axonal varicosities stress-induced decrease in spine number
Impaired spatial learning (Y-maze, water maze), increase in anxiety, increased cued memory of fear conditioning (amygdala dependent) Impaired acquisition of spatial learning (no change in retrieval)
Matrix metalloprotease 9 ICAM-5 (Telencephalin)
Late LTP mediated b1- integrin Early LTP
a3-Integrin
Early and late LTP
Spine density spine enlargement Dendritic spine development induced by MMP-dependent sheding No significant effect
a8-Integrin
LTP
No data
N-cadherin
Late LTP (no effect on early LTP or LTD)
PSA-NCAM
LTP, mossy fiber LTP
Spine size enlargement (no change in spine density); spine maturation when processed by ADAM10 (membrane metalloprotease) Ectopic formation of mossy fiber terminal boutons
resulted in selective interference of late-phase LTP in the CA1 hippocampus (Frey et al., 1996; Huang et al., 1996) (Table 1). The protease cleaves plasminogen to activate plasmin (Mizutani et al., 1997), followed by the activation of pro-brain-derived neurotrophic factor (pro-BDNF) (Pang et al., 2004) and subsequent effects on latephase LTP. tPA also affects late-phase LTP via non-proteolytic action on the low density lipoprotein receptor-related receptor (Fig. 2). The proteolytic activity of MMP-9 is rapidly increased by stimuli that induce late-phase LTP in the CA1 hippocampal subfield. Such regulation requires the activation of NMDA receptors and protein synthesis. Pharmacological experiments have revealed that MMP-9 participates selectively in late-phase LTP but has no role in early phase LTP or LTD (Nagy et al., 2006). MMP-9 cleaves not only ECM proteins (laminin and intercellular adhesion molecule 5) but also growth factors and chemokines (pro-BDNF and tumor necrosis factor (TNF)-a) (Ethell and Ethell, 2007). Thus, local proteolysis by several proteases including neuropsin modifies pre- and/or postsynaptic interactions and precedes signal and morphological changes within the early or late-phase of neural plasticity (Table 1). Intriguingly, each plasticity-related protease has little or no redundancy for their potential substrates, which are presumably localized to the synaptic vicinity, and appears to modulate effectively separate plasticity-related signaling pathways. 8. Perspectives Neural activity-dependent extracellular proteolysis by proteases is a novel molecular mechanism that may relate to learning and memory for the acquisition and storage of newly acquired input in the hippocampus and probably also the prefrontal cortical regions. Physiological evidence suggests that a neuropsin-dependent process contributes to synaptic tagging in weakly stimulated synapses and the conversion of early to late-phase LTP on association with persistently potentiated synapses. Weak stimuli that induce synaptic plasticity of only 90 min may leave a mark (tag), and neuropsin
Impaired fear-conditioning memory (contextual memory) No data
Impaired working memory (nonmatch-to-place T-maze) Normal working memory (nonmatch-to-place T-maze); normal behavioral performance (open field and water maze) No data
Impaired fear-conditioning memory (contextual and cued memory), impaired spatial learning
Huang et al. (1996), Frey et al. (1996), Baranes et al. (1998), Pawlak et al. (2005) Nagy et al. (2006), Wang et al. (2008) Tian et al. (2007), Conant et al. (2010) Chan et al. (2007) Chan et al. (2010)
Bozdagi et al. (2000), Malinverno et al. (2010)
Cremer et al. (1998), Senkov et al. (2006), Kochlamazashvili et al. (2010)
may mark synapses demonstrating early phase LTP. Although further investigations including behavioral studies are necessary to clarify the mechanisms of extracellular-to-intracellular signaling, synaptic tagging, and late association, these novel mechanisms may be particularly developed in highly evolved mammals. Molecular dynamics in the synapse and synaptic cleft must be the focus of studies of proteolysis-based signaling and the monitoring of the neural molecules using free-moving animals must be explored to resolve the question of mammalian cognitive behavior. Proteases, cell adhesion molecules or matrix proteins that participate in Schaffer-collateral- and hippocampus-dependent behavior are listed. Physiological, anatomical and behavioral functions listed here were primarily analyzed by gene knockout or pharmacological experiments. References Attwood, B.K., Bourgognon, J.-M., Patel, S., Mucha, M., Schlavon, E., Strzypiee, A.E., Young, K.W., Shiosaka, S., Korostynski, M., Piechota, M., Przewtocki, R., Pawlak, R., 2011. Neuropsin cleaves EphB2 in the amygdala to control anxiety. Nature 473, 372–377. Baranes, D., Lederfein, D., Huang, Y.Y., Chen, M., Bailey, C.H., Kandel, E.R., 1998. Tissue plasminogen activator contributes to the late phase of LTP and to synaptic growth in the hippocampal mossy fiber pathway. Neuron 21, 813–825. Bernett, M.J., Blaber, S.I., Scarisbrick, I.A., Dhanarajan, P., Thompson, S.M., Blaber, M., 2002. Crystal structure and biochemical characterization of human kallikrein 6 reveals that a trypsin-like kallikrein is expressed in the central nervous system. J. Biol. Chem. 277, 24562–24570. Bozdagi, O., Shan, W., Tanaka, H., Benson, D.L., Huntley, G.W., 2000. Increasing numbers of synaptic puncta during late-phase LTP: N-cadherin is synthesized, recruited to synaptic sites, and required for potentiation. Neuron 28, 245–259. Bozdagi, O., Nagy, V., Kwei, K.T., Huntley, G.W., 2007. In vivo roles for matrix metalloproteinase-9 in mature hippocampal synaptic physiology and plasticity. J. Neurophysiol. 98, 334–344. Chan, C.S., Levenson, J.M., Mukhopadhyay, P.S., Zong, L., Bradley, A., Sweatt, J.D., Davis, R.L., 2007. Alpha3-integrins are required for hippocampal long-term potentiation and working memory. Learn. Mem. 14, 606–615. Chan, C.S., Chen, H., Bradley, A., Dragatsis, I., Rosenmund, C., Davis, R.L., 2010. alpha8-integrins are required for hippocampal long-term potentiation but not for hippocampal-dependent learning. Genes Brain Behav. 9, 402–410.
S. Shiosaka, Y. Ishikawa / Journal of Chemical Neuroanatomy 42 (2011) 24–29 Chen, Z.L., Yoshida, S., Kato, K., Momota, Y., Suzuki, J., Tanaka, T., Ito, J., Nishino, H., Aimoto, S., Kiyama, H., Shiosaka, S., 1995. Expression and activity-dependent changes of a novel limbic-serine protease gene in the hippocampus. J. Neurosci. 15, 5088–5097. Chen, Z.L., Momota, Y., Kato, K., Taniguchi, M., Inoue, N., Shiosaka, S., Yoshida, S., 1998. Expression of neuropsin mRNA in the mouse embryo and the pregnant uterus. J. Histochem. Cytochem. 46, 313–320. Clements, J.A., 2008. Reflections on the tissue kallikrein and kallikrein-related peptidase family – from mice to men – what have we learnt in the last two decades? Biol. Chem. 389, 1447–1454. Conant, K., Wang, Y., Szklarczyk, A., Dudak, A., Mattson, M.P., Lim, S.T., 2010. Matrix metalloproteinase-dependent shedding of intercellular adhesion molecule-5 occurs with long-term potentiation. Neuroscience 166, 508–521. Cremer, H., Chazal, G., Carleton, A., Goridis, C., Vincent, J.D., Lledo, P.M., 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. Davies, B., Kearns, I.R., Ure, J., Davies, C.H., Lathe, R., 2001. Loss of hippocampal serine protease BSP1/neuropsin predisposes to global seizure activity. J. Neurosci. 21, 6993–7000. Debela, M., Magdolen, V., Schechter, N., Valachova, M., Lottspeich, F., Craik, C.S., Choe, Y., Bode, W., Goettig, P., 2006. Specificity profiling of seven human tissue kallikreins reveals individual subsite preferences. J. Biol. Chem. 281, 25678–25688. Dityatev, A., Schachner, M., Sonderegger, P., 2010. The dual role of the extracellular matrix in synaptic plasticity and homeostasis. Nat. Rev. Neurosci. 11, 735–746. Elliott, M.B., Irwin, D.M., Diamandis, E.P., 2006. In silico identification and Bayesian phylogenetic analysis of multiple new mammalian kallikrein gene families. Genomics 88, 591–599. Ethell, I.M., Ethell, D.W., 2007. Matrix metalloproteinases in brain development and remodeling: synaptic functions and targets. J. Neurosci. Res. 85, 2813–2823. Frey, U., Morris, R.G., 1997. Synaptic tagging and long-term potentiation. Nature 385, 533–536. Frey, U., Muller, M., Kuhl, D., 1996. A different form of long-lasting potentiation revealed in tissue plasminogen activator mutant mice. J. Neurosci. 16, 2057–2063. Hirata, A., Yoshida, S., Inoue, N., Matsumoto-Miyai, K., Ninomiya, A., Taniguchi, M., Matsuyama, T., Kato, K., Iizasa, H., Kataoka, Y., Yoshida, N., Shiosaka, S., 2001. Abnormalities of synapses and neurons in the hippocampus of neuropsindeficient mice. Mol. Cell. Neurosci. 17, 600–610. Horii, Y., Yamasaki, N., Miyakawa, T., Shiosaka, S., 2008. Increased anxiety-like behavior in neuropsin (kallikrein-related peptidase 8) gene-deficient mice. Behav. Neurosci. 122, 498–504. Huang, Y.Y., Bach, M.E., Lipp, H.P., Zhuo, M., Wolfer, D.P., Hawkins, R.D., Schoonjans, L., Kandel, E.R., Godfraind, J.M., Mulligan, R., Collen, D., Carmeliet, P., 1996. Mice lacking the gene encoding tissue-type plasminogen activator show a selective interference with late-phase long-term potentiation in both Schaffer collateral and mossy fiber pathways. Proc. Natl. Acad. Sci. U.S.A. 93, 8699–8704. Ishikawa, Y., Horii, Y., Tamura, H., Shiosaka, S., 2008. Neuropsin (KLK8)-dependent and -independent synaptic tagging in the Schaffer-collateral pathway of mouse hippocampus. J. Neurosci. 28, 843–849. Ishikawa Y., Tamura H., Shiosaka S. Diversity of neuropsin (KLK8)-dependent synaptic associativity in the hippocampal pyramidal neuron. J. Physiol. In press, doi:10.1113/jphysiol.2011.206169. Izumi, A., Iijima, Y., Noguchi, H., Numakawa, T., Okada, T., Hori, H., Kato, T., Tatsumi, M., Kosuga, A., Kamijima, K., Asada, T., Arima, K., Saitoh, O., Shiosaka, S., Kunugi, H., 2008. Genetic variations of human neuropsin gene and psychiatric disorders: polymorphism screening and possible association with bipolar disorder and cognitive functions. Neuropsychopharmacology 33, 3237–3245. Kishi, T., Kato, M., Shimizu, T., Kato, K., Matsumoto, K., Yoshida, S., Shiosaka, S., Hakoshima, T., 1999. Crystal structure of neuropsin, a hippocampal protease involved in kindling epileptogenesis. J. Biol. Chem. 274, 4220–4224. Kochlamazashvili, G., Senkov, O., Grebenyuk, S., Robinson, C., Xiao, M.F., Stummeyer, K., Gerardy-Schahn, R., Engel, A.K., Feig, L., Semyanov, A., Suppiramaniam, V., Schachner, M., Dityatev, A., 2010. Neural cell adhesion molecule-associated polysialic acid regulates synaptic plasticity and learning by restraining the signaling through GluN2B-containing NMDA receptors. J. Neurosci. 30, 4171–4183. Komai, S., Matsuyama, T., Matsumoto, K., Kato, K., Kobayashi, M., Imamura, K., Yoshida, S., Ugawa, S., Shiosaka, S., 2000. Neuropsin regulates an early-phase of Schaffer-collateral long-term potentiation in the murine hippocampus. Eur. J. Neurosci. 12, 1479–1486. Krug, M., Lossner, B., Ott, T., 1984. Anisomycin blocks the late phase of long-term potentiation in the dentate gyrus of freely moving rats. Brain Res. Bull. 13, 39–42. Kuwae, K., Matsumoto-Miyai, K., Yoshida, S., Sadayama, T., Yoshikawa, K., Hosokawa, K., Shiosaka, S., 2002. Epidermal expression of serine protease, neuropsin (KLK8) in normal and pathological skin samples. Mol. Pathol. 55, 235–241. Li, Y., Qian, Y.P., Yu, X.J., Wang, Y.Q., Dong, D.G., Sun, W., Ma, R.M., Su, B., 2004. Recent origin of a hominoid-specific splice form of neuropsin, a gene involved in learning and memory. Mol. Biol. Evol. 21, 2111–2115. Lu, Z.X., Peng, J., Su, B., 2007. A human-specific mutation leads to the origin of a novel splice form of neuropsin (KLK8), a gene involved in learning and memory. Hum. Mutat. 28, 978–984. Lundwall, A., Brattsand, M., 2008. Kallikrein-related peptidases. Cell. Mol. Life Sci. 65, 2019–2038. Luthl, A., Laurent, J.P., Figurov, A., Muller, D., Schachner, M., 1994. Hippocampal long-term potentiation and neural cell adhesion molecules L1 and NCAM. Nature 372, 777–779. Malinverno, M., Carta, M., Epis, R., Marcello, E., Verpelli, C., Cattabeni, F., Sala, C., Mulle, C., Di Luca, M., Gardoni, F., 2010. Synaptic localization and activity of
29
ADAM10 regulate excitatory synapses through N-cadherin cleavage. J. Neurosci. 30, 16343–16355. Matsumoto-Miyai, K., Kitagawa, R., Ninomiya, A., Momota, Y., Yoshida, S., Shiosaka, S., 2002. Decidualization induces the expression and activation of an extracellular protease neuropsin in mouse uterus. Biol. Reprod. 67, 1414–1418. Matsumoto-Miyai, K., Ninomiya, A., Yamasaki, H., Tamura, H., Nakamura, Y., Shiosaka, S., 2003. NMDA-dependent proteolysis of presynaptic adhesion molecule L1 in the hippocampus by neuropsin. J. Neurosci. 23, 7727–7736. Mitsui, S., Tsuruoka, N., Yamashiro, K., Nakazato, H., Yamaguchi, N., 1999. A novel form of human neuropsin, a brain-related serine protease, is generated by alternative splicing and is expressed preferentially in human adult brain. Eur. J. Biochem. 260, 627–634. Mizutani, A., Tanaka, T., Saito, H., Matsuki, N., 1997. Postsynaptic blockade of inhibitory postsynaptic currents by plasmin in CA1 pyramidal cells of rat hippocampus. Brain Res. 761, 93–96. Momota, Y., Yoshida, S., Ito, J., Shibata, M., Kato, K., Sakurai, K., Matsumoto, K., Shiosaka, S., 1998. Blockade of neuropsin, a serine protease, ameliorates kindling epilepsy. Eur. J. Neurosci. 10, 760–764. Nagy, V., Bozdagi, O., Matynia, A., Balcerzyk, M., Okulski, P., Dzwonek, J., Costa, R.M., Silva, A.J., Kaczmarek, L., Huntley, G.W., 2006. Matrix metalloproteinase-9 is required for hippocampal late-phase long-term potentiation and memory. J. Neurosci. 26, 1923–1934. Nakagami, Y., Abe, K., Nishiyama, N., Matsuki, N., 2000. Laminin degradation by plasmin regulates long-term potentiation. J. Neurosci. 20, 2003–2010. Nakamura, Y., Tamura, H., Horinouchi, K., Shiosaka, S., 2006. Role of neuropsin in formation and maturation of Schaffer-collateral L1cam-immunoreactive synaptic boutons. J. Cell Sci. 119, 1341–1349. Oka, T., Hakoshima, T., Itakura, M., Yamamori, S., Takahashi, M., Hashimoto, Y., Shiosaka, S., Kato, K., 2002. Role of loop structures of neuropsin in the activity of serine protease and regulated secretion. J. Biol. Chem. 277, 14724–14730. Okabe, A., Momota, Y., Yoshida, S., Hirata, A., Ito, J., Nishino, H., Shiosaka, S., 1996. Kindling induces neuropsin mRNA in the mouse brain. Brain Res. 728, 116–120. Pang, P.T., Teng, H.K., Zaitsev, E., Woo, N.T., Sakata, K., Zhen, S., Teng, K.K., Yung, W.H., Hempstead, B.L., Lu, B., 2004. Cleavage of proBDNF by tPA/plasmin is essential for long-term hippocampal plasticity. Science 306, 487–491. Pawlak, R., Rao, B.S., Melchor, J.P., Chattarji, S., McEwen, B., Strickland, S., 2005. Tissue plasminogen activator and plasminogen mediate stress-induced decline of neuronal and cognitive functions in the mouse hippocampus. Proc. Natl. Acad. Sci. U.S.A. 102, 18201–18206. Qian, Z., Gilbert, M.E., Colicos, M.A., Kandel, E.R., Kuhl, D., 1993. Tissue-plasminogen activator is induced as an immediate-early gene during seizure, kindling and long-term potentiation. Nature 361, 453–457. Schuster, T., Krug, M., Hassan, H., Schachner, M., 1998. Increase in proportion of hippocampal spine synapses expressing neural cell adhesion molecule NCAM180 following long-term potentiation. J. Neurobiol. 37, 359–372. Senkov, O., Sun, M., Weinhold, B., Gerardy-Schahn, R., Schachner, M., Dityatev, A., 2006. Polysialylated neural cell adhesion molecule is involved in induction of long-term potentiation and memory acquisition and consolidation in a fearconditioning paradigm. J. Neurosci. 26, 10888–10898. Shimizu, C., Yoshida, S., Shibata, M., Kato, K., Momota, Y., Matsumoto, K., Shiosaka, T., Midorikawa, R., Kamachi, T., Kawabe, A., Shiosaka, S., 1998. Characterization of recombinant and brain neuropsin, a plasticity-related serine protease. J. Biol. Chem. 273, 11189–11196. Soderling, T.R., Derkach, V.A., 2000. Postsynaptic protein phosphorylation and LTP. Trends Neurosci. 23, 75–80. Stefansson, K., Brattsand, M., Roosterman, D., Kempkes, C., Bocheva, G., Steinhoff, M., Egelrud, T., 2008. Activation of proteinase-activated receptor-2 by human kallikrein-related peptidases. J. Invest. Dermatol. 128, 18–25. Tamura, H., Ishikawa, Y., Hino, N., Maeda, M., Yoshida, S., Kaku, S., Shiosaka, S., 2006. Neuropsin is essential for early processes of memory acquisition and Schaffer collateral long-term potentiation in adult mouse hippocampus in vivo. J. Physiol. 570, 541–551. Tamura, H., Ng, D.C., Tokuda, T., Naoki, H., Nakagawa, T., Mizuno, T., Hatanaka, Y., Ishikawa, Y., Ohta, J., Shiosaka, S., 2008. One-chip sensing device (biomedical photonic LSI) enabled to assess hippocampal steep and gradual up-regulated proteolytic activities. J. Neurosci. Methods 173, 114–120. Terayama, R., Bando, Y., Yamada, M., Yoshida, S., 2005. Involvement of neuropsin in the pathogenesis of experimental autoimmune encephalomyelitis. Glia 52, 108–118. Tian, L., Stefanidakis, M., Ning, L., Van Lint, P., Nyman-Huttunen, H., Libert, C., Itohara, S., Mishina, M., Rauvala, H., Gahmberg, C.G., 2007. Activation of NMDA receptors promotes dendritic spine development through MMP-mediated ICAM-5 cleavage. J. Cell Biol. 178, 687–700. Vandell, A.G., Larson, N., Laxmikanthan, G., Panos, M., Blaber, S.I., Blaber, M., Scarisbrick, I.A., 2008. Protease-activated receptor dependent and independent signaling by kallikreins 1 and 6 in CNS neuron and astroglial cell lines. J. Neurochem. 107, 855–870. Wang, X.B., Bozdagi, O., Nikitczuk, J.S., Zhai, Z.W., Zhou, Q., Huntley, G.W., 2008. Extracellular proteolysis by matrix metalloproteinase-9 drives dendritic spine enlargement and long-term potentiation coordinately. Proc. Natl. Acad. Sci. U.S.A. 105, 19520–19525. Yoshida, S., Shiosaka, S., 1999. Plasticity-related serine proteases in the brain (review). Int. J. Mol. Med. 3, 405–409. Yousef, G.M., Diamandis, E.P., 2003. An overview of the kallikrein gene families in humans and other species: emerging candidate tumour markers. Clin. Biochem. 36, 443–452.
Contents lists available at ScienceDirect
Journal of Chemical Neuroanatomy journal homepage: www.elsevier.com/locate/jchemneu
Review
Neuropsin—A possible modulator of synaptic plasticity Sadao Shiosaka a,b,*, Yasuyuki Ishikawa a a b
Laboratory of Functional Neuroscience, Nara Institute of Science and Technology, 8916-5, Takayama, Ikoma, Nara 630-0192, Japan The CREST program from the Ministry of Education, Culture, Sports, Science, and Technology, Japan
A R T I C L E I N F O
A B S T R A C T
Article history: Received 2 December 2010 Received in revised form 30 May 2011 Accepted 30 May 2011 Available online 6 June 2011
Accumulating evidence has suggested pivotal roles for neural proteases in development, maturation, aging, and cognitive functions. Among such proteases, neuropsin, a kallikrein gene-related (KLK) endoprotease, appears to have a significant plasticity function that has been analyzed primarily in the hippocampal Schaffer-collateral pathway. In this article, after reviewing the general features of neuropsin, its role in Schaffer-collateral synaptic plasticity is discussed in some detail. Enzymatically active neuropsin is necessary to establish the early phase of long-term potentiation (LTP). This type of LTP, which can be elicited by rather weak tetanic stimulation, is significant in synaptic late association between two independent hippocampal synapses. Neuropsin deficiency completely impaired the early phase of LTP, leading to the absence of late associativity. Associations between early and persistent-LTP synapses may be related to mammalian working memory and consequently integration in learning and memory. ß 2011 Elsevier B.V. All rights reserved.
Keywords: KLK8 LTP Serine protease Extracellular matrix Cell adhesion molecules Synaptic tagging
Contents 1. 2. 3. 4. 5. 6. 7. 8.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Expression of KLK8 in the brain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Evolution of KLK8. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Protein structure and zymogen activation of neuropsin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Potential substrates and receptors of neuropsin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Involvement of neuropsin on the early phase of synaptic plasticity, late associativity, and behavioral Little overlap in plasticity roles among neural proteases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Perspectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Introduction The concept that macromolecular cleavage or shedding in the synaptic cleft mediates intracellular signals involved in synaptic functions has become increasing familiar in the field of neuroscience. Reverse-transcription polymerase chain reaction for mouse hippocampal mRNAs using primers designed based on the consensus catalytic domain of secretory serine proteases screened out several protease genes including kallikrein-related
* Corresponding author at: Laboratory of Functional Neuroscience, Nara Institute of Science and Technology (NAIST), 8916-5, Takayama, Ikoma, Nara 630-0192, Japan. Tel.: +81 74372 5410; fax: +81 74372 5419. E-mail address: [email protected] (S. Shiosaka). 0891-0618/$ – see front matter ß 2011 Elsevier B.V. All rights reserved. doi:10.1016/j.jchemneu.2011.05.014
........ ........ ........ ........ ........ memory . ........ ........ ........
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
24 25 25 26 26 27 27 28 28
endopeptidase gene1 (KLK) 8, encoding neuropsin (alternative terminology: TADG-14, bsp1, or ovasin); KLK6, encoding neurosin (alternative terminology: zyme or protease M); and tissue plasminogen activator (tPA)2 (Chen et al., 1995). Currently, accumulating evidence supports pivotal roles of
1 The gene terminology was later unified according to the family of human kallikrein-related peptidase (KLK) genes. In humans, unlike in rodents, 15 homologous KLK genes were aligned in the centromere-distal direction on chromosome 19q13.3-4, regardless of some confusion in their ordering (Yousef and Diamandis, 2003). For an overview of KLK family proteases, current review articles written by Lundwall and Brattsand (2008), and Clements (2008) should be referred to. 2 The significance of tPA in neural plasticity has been described elsewhere: (Qian et al., 1993; Baranes et al., 1998; Yoshida and Shiosaka, 1999; Pawlak et al., 2005).
S. Shiosaka, Y. Ishikawa / Journal of Chemical Neuroanatomy 42 (2011) 24–29
Type1 preproneuropsin SS2
S
SS1
Q
SS6
Ser-protease
T1
H118
Type2 preproneuropsin
D165
S257
Type2 proneuropsin SS2
S
Type1 proneuropsin neuropsin SS5 SS3 SS4
25
T2
SS5 SS3 SS4
SS1
SS6
Ser-protease
Q H118
D165
S257
Fig. 1. Domain structures of human Type 1 and 2 preproneuropsin. H118,D165,S257, amino acids of catalytic triad; S, signal sequence; ser-protease, serine protease domain; SS16, disulfide bond 1-6; T1, type 1 specific domain (GHSRA); T2, type 2 specific domain (CGSLDLLTKLYAENLPCVHLNPQWPSQPSHCPRGWRSNPLPPAAGHSRA); Q, QEDK activity masking peptide.
these neural proteases not only in development, maturation, and aging, but also in higher nervous functions such as cognition. Here, we review the general features of neuropsin and discuss its possible roles in synaptic plasticity, particularly in the hippocampal region. 2. Expression of KLK8 in the brain Under non-pathological conditions, KLK8 (neuropsin gene) is localized mainly to the principal neurons of the limbic brain. In situ hybridization histochemistry for KLK8 demonstrated dense signals in pyramidal neurons of the hippocampal CA1–3 subfields and magnocellular neurons of the lateral/basolateral amygdaloid nucleus (Chen et al., 1995). Significant signals were also observed in pyramidal neurons of the cerebral cortex including prefrontal, cingulate and entorhinal regions. Initial investigation into the physiological effects of neuropsin focused on the main function of the hippocampus, neural plasticity, because KLK8 was observed at the highest density in the pyramidal neurons that compose the main hippocampal neural networks and was clearly regulated in a neural activity-dependent manner (Chen et al., 1995; Okabe et al., 1996). A variety of transcriptional controls through both physiological and nonphysiological activity, such as long-term potentiation (LTP), chemically induced plasticity, kindling epileptogenesis, and experimental encephalitis, have been shown to positively regulate KLK8 gene expression (Yoshida and Shiosaka, 1999). Later experiments have shown that KLK8 is not the neuron-specific gene we initially assumed. In addition to the neural expression described above, KLK8 mRNA was found to be widely expressed in stratified squamous epithelium, lung, thymus, pituitary (Chen et al., 1998), and uterus (Matsumoto-Miyai et al., 2002), as well as in pathological tissues (Kuwae et al., 2002; Terayama et al., 2005). 3. Evolution of KLK8 KLK8 is a member of the KLK multigene family, which is located on a single chromosome, 7B2 in mouse and 19q13.4 in human. Although basic proteolytic enzymes emerged very early in the most primitive organisms, the evolution of KLK-family genes, including KLK8, is a recent phenomenon. In silico investigation of the KLK family indicated that there was no KLK in bird (chicken) or amphibian (African clawed frog) species, but orthologues of KLK5– 15 were found in marsupial species (opossum) (Elliott et al., 2006).
Almost family member genes (KLK1–15) presumably completed in primitive mammals and are thereafter conserved in genomes of mouse, rat, dog, pig, macaque, chimpanzee, orangutan, gorilla, and human. Additionally, some species (i.e., mouse and rat) have an expanded family of genes with genetic diversity (Elliott et al., 2006; Lundwall and Brattsand, 2008). Each member of the multigene family may have evolved through sequence exchanges from a common ancestor and a conserved activity domain, which demonstrated similar trypsin-like catalytic activity toward peptide bonds (Arg-X and Lys-X) (Debela et al., 2006). Although they share similar peptidolytic activity to cleave chromogenic synthetic peptides (Merops peptidase database: http://merops.sanger.ac.uk/), each KLK has developed dissimilar substrate specificity for macromolecules and different tissue-specific expression patterns, and therefore may have discrete physiological functions. KLK8 also emerged in an ancestor of marsupial species and, thereafter, may have evolved independently from other KLKs. Lower mammals, including the mouse, rat, dog and pig, have only one orthologue (type 1 KLK8) in the genome. The limbic-specific expression of KLK8 is well conserved from rodent to human3 under non-pathological conditions. Comparative neuroanatomy has indicated that a primitive cortex and hippocampus emerged in the common ancestor of marsupials and monotremes, and, thereafter, limbic and cortical regions underwent progressive encephalization in mammals. It is intriguing how and why three discrete phenomena, i.e., the emergence of (1) KLK8, (2) target substrate molecules, and (3) complex neural networks in the limbic brain, coevolved in parallel to produce unique mammalian neural plasticity. In addition to type 1 KLK8, Mitsui et al. (1999) identified type 2 KLK8, a splicing variant of type 1, in the human brain. Phylogenic studies revealed that type 2 KLK8 was undetectable in mammalian brains from rodents to nonhuman primates (Li et al., 2004; Lu et al., 2007). In humans, type 2 KLK8 was dominantly expressed over type 1 in adult prefrontal cortical areas as well as in the hippocampus (Lu et al., 2007). However, type 1 and 2 KLK8 potentially produce the same zymogen (proneuropsin) and active enzyme (neuropsin) by the removal of the signal peptide and activity-masking peptide, respectively, and seem to result in a single form of neuropsin (Kishi et al., 1999; Oka et al., 2002) (Fig. 1). Since the effects of neuropsin on early phase LTP, which will be 3 Unpublished data from in situ hybridization histochemistry using postmortem human brain.
26
S. Shiosaka, Y. Ishikawa / Journal of Chemical Neuroanatomy 42 (2011) 24–29
discussed in the following section, depend on its enzymatic activity, detecting a special role for type 2-derived neuropsin in regulating the magnitude of synaptic potentiation may be difficult. The long form of proneuropsin (type 2 proneuropsin) may contribute to another unknown function such as the efficiency of synthesis and/or secretion of the zymogen. A human-specific point mutation triggers the change in splicing pattern, leading to the origin of the novel splice form in the human brain. Lu et al. (2007) suggested the critical involvement of type 2 KLK8 in the development of cognitive function during hominization from nonhuman primate to human. Intriguingly, type 2 KLK8 mRNA was not observed in chimpanzee or orangutan brain in spite of its intact open reading frame (Li et al., 2004). Thus, while it remains a hypothetical consideration, type 2 proneuropsin in the human limbic brain (including hippocampus and prefrontal areas) may contribute to functions related to human-specific (or highly developed) cognitive behavior. This hypothesis may be partially supported by the current analysis of single-nucleotide polymorphisms (SNPs) in the human genome. Izumi et al. (2008) conducted polymorphism screening for the entire human KLK8 and compared allelic and genotypic distributions between SNPs in patients with bipolar disorder and normal controls. They reported a significant allelic association between several SNPs and bipolar disorder. Carrying the risk allele for bipolar disorder was significantly associated with lower verbal IQ score, but, interestingly, no change in performance IQ (Izumi et al., 2008). Thus, genetic variation of the KLK8 gene may be involved in the molecular mechanisms of psychiatric disorders and some aspects of memory and intelligence. 4. Protein structure and zymogen activation of neuropsin All proteases in the KLK family are homologous with (chymo)trypsin and have well-conserved amino acid sequences and structures, particularly in the catalytic domain (Kishi et al., 1999; Bernett et al., 2002; Debela et al., 2006). The crystal structure of (type 1) neuropsin contains a serine protease fold that exhibits chimeric features of trypsin and g-NGF, both of which are part of the S1 family (clan SA) of serine proteases according to the Melops classification (Kishi et al., 1999; Bernett et al., 2002). Six surface loop structures of the protein were found to be essential for the generation of specific enzymatic activity and/or secretion of the enzyme via a regulated secretory pathway (Oka et al., 2002). In addition to the transcriptional regulation of KLK8 described above, increase in the amidolytic activity of neuropsin is regulated by neural activity, with activational processing of the zymogen, proneuropsin. Inactive extracellular proneuropsin, which is produced and secreted by signal peptide removal, was found to undergo activational processing to generate the mature active neuropsin by further removal of the N-terminus activity-masking peptide (QGSK and QEDK in mouse and human, respectively) (Shimizu et al., 1998). The neuropsin-activating enzyme that can remove QXXK has not yet been identified. Plasmin and matrix metalloprotease (MMP)-9 are potent activators from the perspective of substrate specificity, localization to neural tissue, and dependency on neural activity. Our preliminary experiments indicate that plasmin can activate the proneuropsin into neuropsin in vitro (unpublished data). However, further work is necessary to determine potential activators of proneuropsin when LTP-inducible neural activity is transmitted into postsynaptic machinery. The blockade of neuropsin activation critically stopped early phase LTP without any effect on basal synaptic transmission, and LTP-inducing tetanus was shown to activate proneuropsin to the active protease briefly after tetanic stimulation (Komai et al., 2000; Tamura et al., 2006,2008). These data can be interpreted as a sequential signaling cascade following four steps. LTP-inducing
stimulation leads to the activation of N-methyl D-aspartic acid (NMDA) receptor-linked signaling (1), which is followed by transient activation of enzymatically non-active proneuropsin into active neuropsin (2) (Matsumoto-Miyai et al., 2003). This neuropsin activity can cleave substrates to modulate pre- and postsynaptic elements (3) (Matsumoto-Miyai et al., 2003; Attwood et al., 2011). The process finally mediates a-amino-3-hydroxyl-5methyl-4-isoxazole-propionate (AMPA) receptors, which receive LTP-dependent modulation (4) (Tamura et al., 2006). In fact, recombinant active neuropsin itself dose-dependently elicited increased LTP-specific (Ser-831) phosphorylation of the type 1 subunit (GluR1) of the AMPA receptor (Tamura et al., 2006). Similarly, high doses of recombinant neuropsin elicited long-term depression (LTD)-specific (Ser-845) phosphorylation on GluR1. The GluR1 subunit is known to be phosphorylated by Ca2+/calmodulindependent kinase II (CAMKII) or protein kinase C (PKC) at Ser-831, and protein kinase A (PKA) at Ser-845, which are established markers of synaptic plasticity (Soderling and Derkach, 2000). Therefore, neuropsin may have an effect on the same intracellular signaling steps as electric tetanic stimulation and thus mimic such plasticity signaling through the cleavage of appropriate target molecules. 5. Potential substrates and receptors of neuropsin Since consensus sequences cleaved by neuropsin are not yet fully established, screening target macromolecules on the basis of such substrate specificity is difficult. However, some extracellular domains of transmembrane and extracellular matrix proteins have been identified by in vitro assays using randomly selected native or recombinant proteins. Generally, specific cleavage sites are present in or around the fibronectin domain of fibronectin (Shimizu et al., 1998), L1-cell adhesion molecule (L1cam) (Matsumoto-Miyai et al., 2003; Nakamura et al., 2006), and EPH receptor B2 (EphB2; the receptor tyrosine kinase) (Attwood et al., 2011) (Fig. 2). Neural excitation in the hippocampus makes neuropsin to cleave extracellular domain of L1cam. Increased neural activity triggers the rapid activation (a few minutes after stimulation) of proneuropsin in an NMDA receptor-dependent manner. The initiation of enzyme activity coincides with phosphorylation by CAMKII, PKA and PKC within the early LTP period (Soderling and Derkach, 2000; Matsumoto-Miyai et al., 2003). However, unlike these kinases with prolonged activity, neuropsin activity quickly decreases to baseline level after a few more minutes. Because activation is so transient, neuropsin must have a prompt substrate cleavage mechanism that can reach completion during the brief activation period. The activated neuropsin immediately cleaved substrates to release the extracellular domain and thereby to induce Schaffer-collateral LTP in an NMDA receptor-dependent manner (Matsumoto-Miyai et al., 2003). Another recent study investigated cleavage of EphB2 by neuropsin in the lateral amygdaloid nucleus. Increased anxietylike response (cued fear conditioning and elevated plus maze) was observed in neuropsin-deficient mice. Attwood et al. (2011) have shown that neuropsin is involved in stress-related plasticity in the amygdala by the cleavage of EphB2 during stress and the reduction of EphB2-NMDA binding. This event results in the facilitation of NMDA-receptor-dependent gene expression to regulate synaptic regulation and, thus, to control stress-induced anxiety in the amygdala. Neuropsin-driven synaptic modification via synaptic or peri-synaptic proteolysis may facilitate the dynamic interaction of intercellular signaling components during the early period of LTP and in stress-related behavior. Some kallikrein-related peptidases (5 and 14) can induce protease-activated receptor (PAR) signaling in the skin and brain (Stefansson et al., 2008; Vandell et al., 2008). However, there is no evidence to indicate that neuropsin is involved in PAR-related
S. Shiosaka, Y. Ishikawa / Journal of Chemical Neuroanatomy 42 (2011) 24–29
27
Fig. 2. Involvement of neural proteases in synaptic plasticity. Extracellular secretory proteases cleave various CAMs and ECM proteins (solid arrows) and are involved in intracellular signaling (broken arrows) to execute complex synaptic functions (bold letters). Abbreviations: AMPAR, a amino-3-hydroxyl-5-methyl-4-isoxazole-propionate receptor; proBDNF, pro-brain-derived neurotrophic factor; CaMKII, calcium/calmodulin-dependent protein kinase II; early LTP, early-phase of long-term potentiation; ECMs, extracellular matrices; EphB2, EPH receptor B2; L1cam, L1 cell adhesion molecule; late LTP, late-phase of long-term potentiation; LRP, low-density lipoprotein-related receptor; MMP9, matrix metalloprotease 9; NMDAR, N-methyl D-aspartic acid receptor; PKC, protein kinase C; PSD95, postsynaptic density protein 95; tPA, tissue plasminogen activator.
signaling. Neuropsin recombinant protein had no thrombin-like platelet coagulation activity when applied to platelets (Shimizu et al., 1998). Moreover, cells stably expressing the PAR-2 gene did not respond to intracellular Ca2+ mobilization by application of neuropsin (Stefansson et al., 2008). Therefore, neuropsin appears to function via system(s) that are discrete from PAR signaling. 6. Involvement of neuropsin on the early phase of synaptic plasticity, late associativity, and behavioral memory Hippocampal early phase LTP elicited by a weak (one 100-Hz) tetanic stimulus normally fades within 90 min. This form of LTP is independent of protein synthesis. In contrast, late-phase LTP elicited by a strong (four 100-Hz) stimulus lasts >180 min and requires new protein synthesis to persist, thus representing protein synthesisdependent LTP. These two temporal phases of LTP occur independently to establish hyperefficacy in synaptic transmission and are regulated by different signaling systems (Krug et al., 1984). Neuropsin deficiency or infusion of a neuropsin-specific inhibitor or anti-neuropsin monoclonal antibody strongly impaired early phase LTP induced by a single tetanus, but not late-phase LTP induced by a stronger stimulus (four tetani). Thus, the plasticity effects of neuropsin are exclusively significant in early phase LTP and not significant in late-phase LTP (Tamura et al., 2006; Ishikawa et al., 2008). Such remarkable participation by neuropsin in early phase LTP led to its examination in a late associativity protocol based on the theory of synaptic tagging (Frey and Morris, 1997). Neuropsin-dependent early phase LTP can be converted into persistent LTP by association with a synapse at which late-phase LTP is preestablished (Ishikawa et al., 2008, in press). This phenomenon is explained by the hypothetical concept of placing a mark (tag) on sites of weak stimulation at a particular synapse (Frey and Morris, 1997). Because local protein synthesis is not observed in weakly stimulated synapses, the proteins necessary for persistence are likely transported from other transcription and translation sites to tagged synaptic areas (Frey and Morris, 1997). Here, a weakly stimulated synapse can receive and capture newly synthesized synaptic proteins. Through this capturing of synthesized proteins, a weakly stimulated synapse is converted into a persistent LTP synapse (late associativity) without the stimulation required to induce late-phase
LTP. Synaptic tagging and late associativity may be particularly important in non-stressful associative memory and, to some significant degree, is considered neuropsin-dependent (Ishikawa et al., 2008). Since neuropsin is localized to the prefrontal, cingulate, and entorhinal cortices and amygdaloid complex in addition to the hippocampus, it may be reasonable to hypothesize that neuropsin also acts on synaptic association in these brain regions. The early plasticity effect of neuropsin was also apparent in behavioral tests using neuropsin-deficient mice. Spontaneous alternation in the Y-maze is a non-stressful behavioral task regarded as a spatial working memory test. Neuropsin-deficient mice exhibited a lower alternation ratio of path selection than wild-type mice. In the Morris water maze, the mice exhibited mildly impaired learning acquisition. Since stronger stimuli preferentially elicit late-phase LTP, it is reasonable that the water maze task, which is relatively stressful for mice, induced rather mild impairment in knockout mice. Neuropsin deficiency also led to enhanced cued memory in fear conditioning but had no effect on contextual fear memory (Horii et al., 2008). The absence of impairment to context-dependent fear conditioning (hippocampus-dependent memory, tested in the Barnes maze) is consistent with the dependence of contextual memory on late-phase LTP. 7. Little overlap in plasticity roles among neural proteases Although the cleavage/shedding of extracellular proteins by neural proteases has not yet been fully clarified, results obtained to date based on substrate specificities and differences in physiological responses indicate that each protease seems to have separate, nonredundant functions in plasticity. Neural proteases are known to be involved in LTP through the potential cleavage/shedding of cell adhesion molecules (CAMs) and extracellular matrix (ECM) proteins (Qian et al., 1993; Momota et al., 1998; Komai et al., 2000; Nakagami et al., 2000; Nagy et al., 2006; Bozdagi et al., 2007; Dityatev et al., 2010; Malinverno et al., 2010) (Table 1).) Antibodies against CAMs and inhibitors of the substrate binding domain of the neural proteases are also recognized to block LTP (Luthl et al., 1994; Schuster et al., 1998). Several proteases other than neuropsin are also known to be involved in neural plasticity. tPA is a well-characterized protease related to synaptic plasticity. A null mutation of the tPA gene in mice
S. Shiosaka, Y. Ishikawa / Journal of Chemical Neuroanatomy 42 (2011) 24–29
28
Table 1 Molecules in the synaptic cleft involved in early or late LTP. Category Extracellular protease
Cell adhesion or matrix protein
Molecule
LTP type involved in
Involvement in spine morphology change
Type of memory tasks involved in
References
Neuropsin
Early LTP b1integrin-mediated
Smaller synapses increase in L1cam orphan bouton
Hirata et al. (2001), Davies et al. (2001), Tamura et al. (2006), Horii et al. (2008)
Tissue plasminogen activator
Late LTP
Formation of axonal varicosities stress-induced decrease in spine number
Impaired spatial learning (Y-maze, water maze), increase in anxiety, increased cued memory of fear conditioning (amygdala dependent) Impaired acquisition of spatial learning (no change in retrieval)
Matrix metalloprotease 9 ICAM-5 (Telencephalin)
Late LTP mediated b1- integrin Early LTP
a3-Integrin
Early and late LTP
Spine density spine enlargement Dendritic spine development induced by MMP-dependent sheding No significant effect
a8-Integrin
LTP
No data
N-cadherin
Late LTP (no effect on early LTP or LTD)
PSA-NCAM
LTP, mossy fiber LTP
Spine size enlargement (no change in spine density); spine maturation when processed by ADAM10 (membrane metalloprotease) Ectopic formation of mossy fiber terminal boutons
resulted in selective interference of late-phase LTP in the CA1 hippocampus (Frey et al., 1996; Huang et al., 1996) (Table 1). The protease cleaves plasminogen to activate plasmin (Mizutani et al., 1997), followed by the activation of pro-brain-derived neurotrophic factor (pro-BDNF) (Pang et al., 2004) and subsequent effects on latephase LTP. tPA also affects late-phase LTP via non-proteolytic action on the low density lipoprotein receptor-related receptor (Fig. 2). The proteolytic activity of MMP-9 is rapidly increased by stimuli that induce late-phase LTP in the CA1 hippocampal subfield. Such regulation requires the activation of NMDA receptors and protein synthesis. Pharmacological experiments have revealed that MMP-9 participates selectively in late-phase LTP but has no role in early phase LTP or LTD (Nagy et al., 2006). MMP-9 cleaves not only ECM proteins (laminin and intercellular adhesion molecule 5) but also growth factors and chemokines (pro-BDNF and tumor necrosis factor (TNF)-a) (Ethell and Ethell, 2007). Thus, local proteolysis by several proteases including neuropsin modifies pre- and/or postsynaptic interactions and precedes signal and morphological changes within the early or late-phase of neural plasticity (Table 1). Intriguingly, each plasticity-related protease has little or no redundancy for their potential substrates, which are presumably localized to the synaptic vicinity, and appears to modulate effectively separate plasticity-related signaling pathways. 8. Perspectives Neural activity-dependent extracellular proteolysis by proteases is a novel molecular mechanism that may relate to learning and memory for the acquisition and storage of newly acquired input in the hippocampus and probably also the prefrontal cortical regions. Physiological evidence suggests that a neuropsin-dependent process contributes to synaptic tagging in weakly stimulated synapses and the conversion of early to late-phase LTP on association with persistently potentiated synapses. Weak stimuli that induce synaptic plasticity of only 90 min may leave a mark (tag), and neuropsin
Impaired fear-conditioning memory (contextual memory) No data
Impaired working memory (nonmatch-to-place T-maze) Normal working memory (nonmatch-to-place T-maze); normal behavioral performance (open field and water maze) No data
Impaired fear-conditioning memory (contextual and cued memory), impaired spatial learning
Huang et al. (1996), Frey et al. (1996), Baranes et al. (1998), Pawlak et al. (2005) Nagy et al. (2006), Wang et al. (2008) Tian et al. (2007), Conant et al. (2010) Chan et al. (2007) Chan et al. (2010)
Bozdagi et al. (2000), Malinverno et al. (2010)
Cremer et al. (1998), Senkov et al. (2006), Kochlamazashvili et al. (2010)
may mark synapses demonstrating early phase LTP. Although further investigations including behavioral studies are necessary to clarify the mechanisms of extracellular-to-intracellular signaling, synaptic tagging, and late association, these novel mechanisms may be particularly developed in highly evolved mammals. Molecular dynamics in the synapse and synaptic cleft must be the focus of studies of proteolysis-based signaling and the monitoring of the neural molecules using free-moving animals must be explored to resolve the question of mammalian cognitive behavior. Proteases, cell adhesion molecules or matrix proteins that participate in Schaffer-collateral- and hippocampus-dependent behavior are listed. Physiological, anatomical and behavioral functions listed here were primarily analyzed by gene knockout or pharmacological experiments. References Attwood, B.K., Bourgognon, J.-M., Patel, S., Mucha, M., Schlavon, E., Strzypiee, A.E., Young, K.W., Shiosaka, S., Korostynski, M., Piechota, M., Przewtocki, R., Pawlak, R., 2011. Neuropsin cleaves EphB2 in the amygdala to control anxiety. Nature 473, 372–377. Baranes, D., Lederfein, D., Huang, Y.Y., Chen, M., Bailey, C.H., Kandel, E.R., 1998. Tissue plasminogen activator contributes to the late phase of LTP and to synaptic growth in the hippocampal mossy fiber pathway. Neuron 21, 813–825. Bernett, M.J., Blaber, S.I., Scarisbrick, I.A., Dhanarajan, P., Thompson, S.M., Blaber, M., 2002. Crystal structure and biochemical characterization of human kallikrein 6 reveals that a trypsin-like kallikrein is expressed in the central nervous system. J. Biol. Chem. 277, 24562–24570. Bozdagi, O., Shan, W., Tanaka, H., Benson, D.L., Huntley, G.W., 2000. Increasing numbers of synaptic puncta during late-phase LTP: N-cadherin is synthesized, recruited to synaptic sites, and required for potentiation. Neuron 28, 245–259. Bozdagi, O., Nagy, V., Kwei, K.T., Huntley, G.W., 2007. In vivo roles for matrix metalloproteinase-9 in mature hippocampal synaptic physiology and plasticity. J. Neurophysiol. 98, 334–344. Chan, C.S., Levenson, J.M., Mukhopadhyay, P.S., Zong, L., Bradley, A., Sweatt, J.D., Davis, R.L., 2007. Alpha3-integrins are required for hippocampal long-term potentiation and working memory. Learn. Mem. 14, 606–615. Chan, C.S., Chen, H., Bradley, A., Dragatsis, I., Rosenmund, C., Davis, R.L., 2010. alpha8-integrins are required for hippocampal long-term potentiation but not for hippocampal-dependent learning. Genes Brain Behav. 9, 402–410.
S. Shiosaka, Y. Ishikawa / Journal of Chemical Neuroanatomy 42 (2011) 24–29 Chen, Z.L., Yoshida, S., Kato, K., Momota, Y., Suzuki, J., Tanaka, T., Ito, J., Nishino, H., Aimoto, S., Kiyama, H., Shiosaka, S., 1995. Expression and activity-dependent changes of a novel limbic-serine protease gene in the hippocampus. J. Neurosci. 15, 5088–5097. Chen, Z.L., Momota, Y., Kato, K., Taniguchi, M., Inoue, N., Shiosaka, S., Yoshida, S., 1998. Expression of neuropsin mRNA in the mouse embryo and the pregnant uterus. J. Histochem. Cytochem. 46, 313–320. Clements, J.A., 2008. Reflections on the tissue kallikrein and kallikrein-related peptidase family – from mice to men – what have we learnt in the last two decades? Biol. Chem. 389, 1447–1454. Conant, K., Wang, Y., Szklarczyk, A., Dudak, A., Mattson, M.P., Lim, S.T., 2010. Matrix metalloproteinase-dependent shedding of intercellular adhesion molecule-5 occurs with long-term potentiation. Neuroscience 166, 508–521. Cremer, H., Chazal, G., Carleton, A., Goridis, C., Vincent, J.D., Lledo, P.M., 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. Davies, B., Kearns, I.R., Ure, J., Davies, C.H., Lathe, R., 2001. Loss of hippocampal serine protease BSP1/neuropsin predisposes to global seizure activity. J. Neurosci. 21, 6993–7000. Debela, M., Magdolen, V., Schechter, N., Valachova, M., Lottspeich, F., Craik, C.S., Choe, Y., Bode, W., Goettig, P., 2006. Specificity profiling of seven human tissue kallikreins reveals individual subsite preferences. J. Biol. Chem. 281, 25678–25688. Dityatev, A., Schachner, M., Sonderegger, P., 2010. The dual role of the extracellular matrix in synaptic plasticity and homeostasis. Nat. Rev. Neurosci. 11, 735–746. Elliott, M.B., Irwin, D.M., Diamandis, E.P., 2006. In silico identification and Bayesian phylogenetic analysis of multiple new mammalian kallikrein gene families. Genomics 88, 591–599. Ethell, I.M., Ethell, D.W., 2007. Matrix metalloproteinases in brain development and remodeling: synaptic functions and targets. J. Neurosci. Res. 85, 2813–2823. Frey, U., Morris, R.G., 1997. Synaptic tagging and long-term potentiation. Nature 385, 533–536. Frey, U., Muller, M., Kuhl, D., 1996. A different form of long-lasting potentiation revealed in tissue plasminogen activator mutant mice. J. Neurosci. 16, 2057–2063. Hirata, A., Yoshida, S., Inoue, N., Matsumoto-Miyai, K., Ninomiya, A., Taniguchi, M., Matsuyama, T., Kato, K., Iizasa, H., Kataoka, Y., Yoshida, N., Shiosaka, S., 2001. Abnormalities of synapses and neurons in the hippocampus of neuropsindeficient mice. Mol. Cell. Neurosci. 17, 600–610. Horii, Y., Yamasaki, N., Miyakawa, T., Shiosaka, S., 2008. Increased anxiety-like behavior in neuropsin (kallikrein-related peptidase 8) gene-deficient mice. Behav. Neurosci. 122, 498–504. Huang, Y.Y., Bach, M.E., Lipp, H.P., Zhuo, M., Wolfer, D.P., Hawkins, R.D., Schoonjans, L., Kandel, E.R., Godfraind, J.M., Mulligan, R., Collen, D., Carmeliet, P., 1996. Mice lacking the gene encoding tissue-type plasminogen activator show a selective interference with late-phase long-term potentiation in both Schaffer collateral and mossy fiber pathways. Proc. Natl. Acad. Sci. U.S.A. 93, 8699–8704. Ishikawa, Y., Horii, Y., Tamura, H., Shiosaka, S., 2008. Neuropsin (KLK8)-dependent and -independent synaptic tagging in the Schaffer-collateral pathway of mouse hippocampus. J. Neurosci. 28, 843–849. Ishikawa Y., Tamura H., Shiosaka S. Diversity of neuropsin (KLK8)-dependent synaptic associativity in the hippocampal pyramidal neuron. J. Physiol. In press, doi:10.1113/jphysiol.2011.206169. Izumi, A., Iijima, Y., Noguchi, H., Numakawa, T., Okada, T., Hori, H., Kato, T., Tatsumi, M., Kosuga, A., Kamijima, K., Asada, T., Arima, K., Saitoh, O., Shiosaka, S., Kunugi, H., 2008. Genetic variations of human neuropsin gene and psychiatric disorders: polymorphism screening and possible association with bipolar disorder and cognitive functions. Neuropsychopharmacology 33, 3237–3245. Kishi, T., Kato, M., Shimizu, T., Kato, K., Matsumoto, K., Yoshida, S., Shiosaka, S., Hakoshima, T., 1999. Crystal structure of neuropsin, a hippocampal protease involved in kindling epileptogenesis. J. Biol. Chem. 274, 4220–4224. Kochlamazashvili, G., Senkov, O., Grebenyuk, S., Robinson, C., Xiao, M.F., Stummeyer, K., Gerardy-Schahn, R., Engel, A.K., Feig, L., Semyanov, A., Suppiramaniam, V., Schachner, M., Dityatev, A., 2010. Neural cell adhesion molecule-associated polysialic acid regulates synaptic plasticity and learning by restraining the signaling through GluN2B-containing NMDA receptors. J. Neurosci. 30, 4171–4183. Komai, S., Matsuyama, T., Matsumoto, K., Kato, K., Kobayashi, M., Imamura, K., Yoshida, S., Ugawa, S., Shiosaka, S., 2000. Neuropsin regulates an early-phase of Schaffer-collateral long-term potentiation in the murine hippocampus. Eur. J. Neurosci. 12, 1479–1486. Krug, M., Lossner, B., Ott, T., 1984. Anisomycin blocks the late phase of long-term potentiation in the dentate gyrus of freely moving rats. Brain Res. Bull. 13, 39–42. Kuwae, K., Matsumoto-Miyai, K., Yoshida, S., Sadayama, T., Yoshikawa, K., Hosokawa, K., Shiosaka, S., 2002. Epidermal expression of serine protease, neuropsin (KLK8) in normal and pathological skin samples. Mol. Pathol. 55, 235–241. Li, Y., Qian, Y.P., Yu, X.J., Wang, Y.Q., Dong, D.G., Sun, W., Ma, R.M., Su, B., 2004. Recent origin of a hominoid-specific splice form of neuropsin, a gene involved in learning and memory. Mol. Biol. Evol. 21, 2111–2115. Lu, Z.X., Peng, J., Su, B., 2007. A human-specific mutation leads to the origin of a novel splice form of neuropsin (KLK8), a gene involved in learning and memory. Hum. Mutat. 28, 978–984. Lundwall, A., Brattsand, M., 2008. Kallikrein-related peptidases. Cell. Mol. Life Sci. 65, 2019–2038. Luthl, A., Laurent, J.P., Figurov, A., Muller, D., Schachner, M., 1994. Hippocampal long-term potentiation and neural cell adhesion molecules L1 and NCAM. Nature 372, 777–779. Malinverno, M., Carta, M., Epis, R., Marcello, E., Verpelli, C., Cattabeni, F., Sala, C., Mulle, C., Di Luca, M., Gardoni, F., 2010. Synaptic localization and activity of
29
ADAM10 regulate excitatory synapses through N-cadherin cleavage. J. Neurosci. 30, 16343–16355. Matsumoto-Miyai, K., Kitagawa, R., Ninomiya, A., Momota, Y., Yoshida, S., Shiosaka, S., 2002. Decidualization induces the expression and activation of an extracellular protease neuropsin in mouse uterus. Biol. Reprod. 67, 1414–1418. Matsumoto-Miyai, K., Ninomiya, A., Yamasaki, H., Tamura, H., Nakamura, Y., Shiosaka, S., 2003. NMDA-dependent proteolysis of presynaptic adhesion molecule L1 in the hippocampus by neuropsin. J. Neurosci. 23, 7727–7736. Mitsui, S., Tsuruoka, N., Yamashiro, K., Nakazato, H., Yamaguchi, N., 1999. A novel form of human neuropsin, a brain-related serine protease, is generated by alternative splicing and is expressed preferentially in human adult brain. Eur. J. Biochem. 260, 627–634. Mizutani, A., Tanaka, T., Saito, H., Matsuki, N., 1997. Postsynaptic blockade of inhibitory postsynaptic currents by plasmin in CA1 pyramidal cells of rat hippocampus. Brain Res. 761, 93–96. Momota, Y., Yoshida, S., Ito, J., Shibata, M., Kato, K., Sakurai, K., Matsumoto, K., Shiosaka, S., 1998. Blockade of neuropsin, a serine protease, ameliorates kindling epilepsy. Eur. J. Neurosci. 10, 760–764. Nagy, V., Bozdagi, O., Matynia, A., Balcerzyk, M., Okulski, P., Dzwonek, J., Costa, R.M., Silva, A.J., Kaczmarek, L., Huntley, G.W., 2006. Matrix metalloproteinase-9 is required for hippocampal late-phase long-term potentiation and memory. J. Neurosci. 26, 1923–1934. Nakagami, Y., Abe, K., Nishiyama, N., Matsuki, N., 2000. Laminin degradation by plasmin regulates long-term potentiation. J. Neurosci. 20, 2003–2010. Nakamura, Y., Tamura, H., Horinouchi, K., Shiosaka, S., 2006. Role of neuropsin in formation and maturation of Schaffer-collateral L1cam-immunoreactive synaptic boutons. J. Cell Sci. 119, 1341–1349. Oka, T., Hakoshima, T., Itakura, M., Yamamori, S., Takahashi, M., Hashimoto, Y., Shiosaka, S., Kato, K., 2002. Role of loop structures of neuropsin in the activity of serine protease and regulated secretion. J. Biol. Chem. 277, 14724–14730. Okabe, A., Momota, Y., Yoshida, S., Hirata, A., Ito, J., Nishino, H., Shiosaka, S., 1996. Kindling induces neuropsin mRNA in the mouse brain. Brain Res. 728, 116–120. Pang, P.T., Teng, H.K., Zaitsev, E., Woo, N.T., Sakata, K., Zhen, S., Teng, K.K., Yung, W.H., Hempstead, B.L., Lu, B., 2004. Cleavage of proBDNF by tPA/plasmin is essential for long-term hippocampal plasticity. Science 306, 487–491. Pawlak, R., Rao, B.S., Melchor, J.P., Chattarji, S., McEwen, B., Strickland, S., 2005. Tissue plasminogen activator and plasminogen mediate stress-induced decline of neuronal and cognitive functions in the mouse hippocampus. Proc. Natl. Acad. Sci. U.S.A. 102, 18201–18206. Qian, Z., Gilbert, M.E., Colicos, M.A., Kandel, E.R., Kuhl, D., 1993. Tissue-plasminogen activator is induced as an immediate-early gene during seizure, kindling and long-term potentiation. Nature 361, 453–457. Schuster, T., Krug, M., Hassan, H., Schachner, M., 1998. Increase in proportion of hippocampal spine synapses expressing neural cell adhesion molecule NCAM180 following long-term potentiation. J. Neurobiol. 37, 359–372. Senkov, O., Sun, M., Weinhold, B., Gerardy-Schahn, R., Schachner, M., Dityatev, A., 2006. Polysialylated neural cell adhesion molecule is involved in induction of long-term potentiation and memory acquisition and consolidation in a fearconditioning paradigm. J. Neurosci. 26, 10888–10898. Shimizu, C., Yoshida, S., Shibata, M., Kato, K., Momota, Y., Matsumoto, K., Shiosaka, T., Midorikawa, R., Kamachi, T., Kawabe, A., Shiosaka, S., 1998. Characterization of recombinant and brain neuropsin, a plasticity-related serine protease. J. Biol. Chem. 273, 11189–11196. Soderling, T.R., Derkach, V.A., 2000. Postsynaptic protein phosphorylation and LTP. Trends Neurosci. 23, 75–80. Stefansson, K., Brattsand, M., Roosterman, D., Kempkes, C., Bocheva, G., Steinhoff, M., Egelrud, T., 2008. Activation of proteinase-activated receptor-2 by human kallikrein-related peptidases. J. Invest. Dermatol. 128, 18–25. Tamura, H., Ishikawa, Y., Hino, N., Maeda, M., Yoshida, S., Kaku, S., Shiosaka, S., 2006. Neuropsin is essential for early processes of memory acquisition and Schaffer collateral long-term potentiation in adult mouse hippocampus in vivo. J. Physiol. 570, 541–551. Tamura, H., Ng, D.C., Tokuda, T., Naoki, H., Nakagawa, T., Mizuno, T., Hatanaka, Y., Ishikawa, Y., Ohta, J., Shiosaka, S., 2008. One-chip sensing device (biomedical photonic LSI) enabled to assess hippocampal steep and gradual up-regulated proteolytic activities. J. Neurosci. Methods 173, 114–120. Terayama, R., Bando, Y., Yamada, M., Yoshida, S., 2005. Involvement of neuropsin in the pathogenesis of experimental autoimmune encephalomyelitis. Glia 52, 108–118. Tian, L., Stefanidakis, M., Ning, L., Van Lint, P., Nyman-Huttunen, H., Libert, C., Itohara, S., Mishina, M., Rauvala, H., Gahmberg, C.G., 2007. Activation of NMDA receptors promotes dendritic spine development through MMP-mediated ICAM-5 cleavage. J. Cell Biol. 178, 687–700. Vandell, A.G., Larson, N., Laxmikanthan, G., Panos, M., Blaber, S.I., Blaber, M., Scarisbrick, I.A., 2008. Protease-activated receptor dependent and independent signaling by kallikreins 1 and 6 in CNS neuron and astroglial cell lines. J. Neurochem. 107, 855–870. Wang, X.B., Bozdagi, O., Nikitczuk, J.S., Zhai, Z.W., Zhou, Q., Huntley, G.W., 2008. Extracellular proteolysis by matrix metalloproteinase-9 drives dendritic spine enlargement and long-term potentiation coordinately. Proc. Natl. Acad. Sci. U.S.A. 105, 19520–19525. Yoshida, S., Shiosaka, S., 1999. Plasticity-related serine proteases in the brain (review). Int. J. Mol. Med. 3, 405–409. Yousef, G.M., Diamandis, E.P., 2003. An overview of the kallikrein gene families in humans and other species: emerging candidate tumour markers. Clin. Biochem. 36, 443–452.