- Email: [email protected]
Molecular diversity underlying cortical excitatory and inhibitory synapse development
Available online at www.sciencedirect.com
ScienceDirect Molecular diversity underlying cortical excitatory and inhibitory synapse development Emilia Favuzzi1,2,3 and Beatriz Rico1,2 The complexity and precision of cortical circuitries is achieved during development due to the exquisite diversity of synapse types that is generated in a highly regulated manner. Here, we review the recent increase in our understanding of how synapse type-specific molecules differentially regulate the development of excitatory and inhibitory synapses. Moreover, several synapse subtype-specific molecules have been shown to control the targeting, formation or maturation of particular subtypes of excitatory synapses. Because inhibitory neurons are extremely diverse, a similar molecular diversity is likely to underlie the development of different inhibitory synapses making it a promising topic for future investigation in the field of the synapse development.
Addresses 1 Centre for Developmental Neurobiology, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London SE1 1UL, United Kingdom 2 MRC Centre for Neurodevelopmental Disorders, King’s College London, London SE1 1UL, United Kingdom Corresponding author: Present address: Broad Institute, Stanley Center for Psychiatric Research, Cambridge, MA 02142 and Harvard Medical School, Department of Neurobiology, Boston, MA 02115, USA.
3
types which fall in two broad categories: excitatory pyramidal neurons and inhibitory GABAergic interneurons. The elaborate but partially stereotyped connectivity patterns of different neuronal types are perfectly suited to fulfill specific functional roles and underlie the cortex’s unique computational prowess [1]. Such specificity implies not only cellular but also synaptic diversity that is built upon molecular diversity and emerges through a tightly regulated sequence of developmental processes. Each of these steps gradually restricts the number of potential synaptic partners and further sculpts specific synaptic properties. Regardless of its multiplicity, it is generally agreed that synapse development involves two broad sequential phases. First, mostly genetically determined processes lead to a transient and relatively nonspecific contact that is stabilized by molecular interactions. Afterward, during synapse maturation, a series of progressively more activity-dependent processes kick in. In this review, we will focus on the developmental molecular mechanisms that generate synapse diversity in the cerebral cortex, with a particular emphasis on the differences and similarities existing between excitatory and inhibitory synapses.
Current Opinion in Neurobiology 2018, 53:8–15 This review comes from a themed issue on Developmental neuroscience Edited by Alex Kolodkin and Guillermina Lo´pez-Bendito
https://doi.org/10.1016/j.conb.2018.03.011 0959-4388/ã 2018 Elsevier Ltd. All rights reserved.
Introduction From both an evolutionary and a developmental perspective, brain wiring reaches an exceptional level of complexity in the cerebral cortex. The precision that characterizes this process is truly astonishing and even more so if one considers its outcome, us. Cortical circuitries, honed over hundreds of million years of evolution, are composed of an interconnected multitude of neuronal cell 4
4. Title freely adapted from Oscar Wilde’s 1895 play ‘The Importance of Being Earnest’. The importance of being Axon4: first contact between synaptic partners Axons terminals are endowed with the ability to discriminate their correct synaptic targets among a dense array of potential partners. A key role in mediating the first contact between synaptic partners is played by transmembrane cell adhesion molecules (CAMs) that serve both as permissive adhesion substrates and as recognition tags. For example, distinct cadherins and leucine-rich repeat (LRR) proteins are expressed in different cell types and can regulate input-specific target selection [2,3]. Classical guidance cues like Semaphorins and their receptor neuropilins have been associated with proximal and distal pyramidal cell dendritic targeting [4]. In addition, recent work showed that the cell-adhesion G protein-coupled receptor of alpha-latrotoxin latrophilin-1 and the transmembrane protein teneurin-3 are required for the specific targeting of entorhinal cortex afferents to CA1 pyramidal dendrites and CA1 hippocampal axons to distal subiculum, respectively [5,6].
Title freely adapted from Oscar Wilde’s 1895 play ‘The Importance of Being Earnest’.
Current Opinion in Neurobiology 2018, 53:8–15
www.sciencedirect.com
Cortical excitatory and inhibitory synapse formation Favuzzi and Rico 9
Cortical inhibitory neurons also exhibit exquisite target specificity. A classic example is represented by SSTpositive Martinotti cells, which are particularly abundant in neocortical layer V and possess ascending axons that arborize in layer I where they establish synapses onto the dendritic tufts of pyramidal neurons [7]. In the cerebellum, chemoaffinity-based recognition strategies ensure the correct targeting of inhibitory axons [8]. Although it is possible that similar mechanisms function across different cortices, the molecules regulating inhibitory target specificity in the cerebral cortex still await discovery.
5. Title freely adapted from Oscar Wilde’s 1895 play ‘An Ideal Husband’.An Ideal Husband, Act I5: forming a synapse Once matching synaptic partners are in contact, a coordinated assembly of molecules on both sides of the synapse takes place. This is mediated by synaptic organizers which, in addition to having a cohesive role, initiate bidirectional trans-synaptic signaling events that trigger a near-complete program for pre-synaptic and post-synaptic differentiation [9]. The best example of cell adhesion molecules with both adhesive and inducing function at synapses are neuroligins and neurexins [10]. The elegant experiment that led to the discovery of the neuroligins and neurexins as potent inducers of synapse formation has become a ‘classic’ of neuroscience and paved the way for the discovery of several other synaptogenic adhesion complexes, such as the cell adhesion molecule SynCAM [11] or members of the leucine-rich repeat (LRR) family of cell adhesion proteins [2]. Although most synaptic organizers are ubiquitously expressed, the exceptional diversity of isoforms, ligands and interactors that they can combine in a cell-specific or circuit-specific manner critically contributes to generating synapse diversity (Figure 1). For instance, different neurexin isoforms exhibit a cell-type specific expression and pan-neurexin deletion produces dramatically diverse phenotypes at different types of synapses [12–14]. Another example is provided by how different neuroligin splice variants selectively induce glutamatergic or GABAergic presynaptic differentiation, likely through specific trans-synaptic interactions with Neurexins [15]. Selectivity may be further achieved by recruiting synapse type-specific molecules, as is the case for Neuroligin 2 which by interacting with Gephyrin recruits Gephyrin-associated proteins to inhibitory postsynapses [16]. In addition to ubiquitous synaptogenic complexes, several synapse type-specific organizers have also been identified. Although nearly all of them promote only 5
Title freely adapted from Oscar Wilde’s 1895 play ‘An Ideal Husband’. www.sciencedirect.com
excitatory synapse development [17–21], Sema4D-PlexinB1, Slitrk3-PTPd and Neurexin2a-IgSF21 were identified as trans-synaptic organizing complexes selectively required for GABAergic synapse development [22,23,24]. Interestingly, recent work showed that, despite having inducing properties, both Slitrk3 and Sema4D act in a second phase of synapse formation. In particular, Slitrk3 functions in a hierarchical and synergistic manner after Neuroligin 2 initiates the synaptic assembly [25] and Sema4D induces remodeling of the actin cytoskeleton and consequent bouton stabilization [26]. Similarly, C1q-like proteins belong to a family of extracellular synaptic organizers and have been recently shown to recruit functional postsynaptic kainate-type glutamate receptors complexes during synapse maturation (Figure 2) [27,28]. These recent findings suggest that the line traced between synapse formation and maturation is likely to be less clear-cut than what is often assumed for the sake of description. Most synaptogenic molecules discovered so far are transmembrane adhesion molecules. However, members of the fibroblast growth factor (FGF) family have been shown to act as soluble target-derived presynaptic organizers that induce clustering of synaptic vesicles and differentiation of the presynaptic specialization [29]. Interestingly, the synaptogenic function of FGFs is synapse type-specific: FGF22 and FGF7 promote the differentiation of excitatory and inhibitory presynaptic terminals, respectively [30]. In addition to synaptic organizers, cell type-specific molecules that have adhesive but not inducing properties also contribute to synapse specificity by dictating whether a transient contact is transformed in a synapse or not. An excellent example of this selective synaptogenesis onto correct targets is how cadherin-9 regulates preferential synapse formation — rather than axon targeting — of dentate gyrus (DG) axons onto CA3 but not CA1 pyramidal neurons in the hippocampus [31].
An Ideal Husband, Act II: synapse maturation Excitatory and inhibitory synapses are constantly generated at a high rate in the developing cortex. Newborn synapses are functional but immature. Subsequently, a combination of genetically predetermined developmental programs [32–34] and activity-dependent processes mediates synapse maturation [35]. The maturation of a synapse involves structural and functional changes that are intimately related to both an increased efficacy of presynaptic neurotransmitter release and a mature profile of postsynaptic receptors. The basic organizing principles of synapse maturation hold true for both excitatory and inhibitory synapses (Figure 2). A critical step in this process is the recruitment of scaffolding proteins, abundant and essential Current Opinion in Neurobiology 2018, 53:8–15
10 Developmental neuroscience
Figure 1
Synapse formation Excitatory synapses
Inhibitory synapses
Cdh9 HSPG NRX1β4(–) LAR Glypican PTPσ LRRTM4 FGF22
Slitrk2
NRX1β4(+) PLXNB1 PTPδ NRX2α NRX1α4(–)
NGL-3 NL1BTrkC LRRTM2 FGF7
Pyramidal cell
NL2A NL2A Slitrk3 IgSF21 Sema4D
Current Opinion in Neurobiology
Molecular diversity supports the formation of excitatory and inhibitory synapses. Synapse-type specific organizers, adhesion molecules and targetderived soluble factors generate the very first differences between excitatory and inhibitory synapses during their formation. Due to their high number, not all molecules specifically involved in the formation of excitatory synapses are shown. Note also that proteins that regulate the formation of both excitatory and inhibitory synapses have been excluded from the schematic.
components of the postsynaptic specialization [36]. Scaffold proteins anchor neurotransmitter receptors and adhesion molecules and link them with downstream signaling proteins. At the excitatory synapses, such scaffold proteins include the membrane-associated guanylate kinases (MAGUKs), among which prominent in synapse maturation is the role of PSD95 [37,38]. Likewise, the scaffold protein gephyrin and several gephyrin-associated proteins are recruited to the inhibitory synapses [39]. Another structural element that undergoes profound remodeling on both sides of the maturing excitatory as well as inhibitory synapses is the cytoskeleton. Recent work showed that the F-actin binding protein a-actinin anchors PSD-95 at the excitatory postsynapse [40]. In contrast, the exact molecular mechanisms by which gephyrin is targeted and clustered to inhibitory synapses are not well understood [39]. Presynaptically, the cytoskeletal structure supports the organization of the active zone which displays some degree of molecular heterogeneity at different types of synapses [26,41–43]. Synapse maturation also involves the incorporation of clusters of AMPA (for excitatory synapses) and GABAA (for inhibitory synapses) receptors. The importance of Current Opinion in Neurobiology 2018, 53:8–15
this step has been well studied for glutamatergic synapse maturation. Synaptic accumulation of AMPA receptors (AMPARs) leads to the simultaneous activation of NMDA receptors (NMDARs) and to the potentiation of immature synapses [44]. Most molecules that selectively regulate excitatory synapse maturation play a role precisely in the clustering, trafficking or synaptic delivery of AMPARs, further underscoring its prominence [45–47,48,49,50]. Although less studied, regulation of GABAA receptor (GABAAR) trafficking has been shown to modulate inhibitory synaptic strength in a relatively similar way. In fact, two recently discovered molecules, GARLH family proteins and Clptm1, involved in controlling the trafficking and synaptic localization of GABAARs, respectively, critically regulate inhibitory synaptic transmission [51,52]. Another aspect of synapse maturation in which cell typeselective proteins contribute to synapse diversity is the determination of synaptic properties. One excellent — and to our knowledge still unique — example is the target-induced differences in presynaptic release properties of CA1 pyramidal cell excitatory synapses. As a result of the postsynaptic expression of the LRR protein Elfn1, synapses made onto somatostatin-positive (SST www.sciencedirect.com
Cortical excitatory and inhibitory synapse formation Favuzzi and Rico 11
Figure 2
Synapse maturation Excitatory synapses
Inhibitory synapses F-actin SIRPα LGI1 AMPAR
SynDIG1 AMPAR SALM2 PSD95 ADAM22 α-actinin IgSF11
NRX3β4+SS525b C1qI2/3 KAR
F-actin
MET
NMDAR PlexinB1 Sema4D
ErbB4 GABA R
Gephyrin
Pyramidal cell
Clptm1
F-actin GARLH Current Opinion in Neurobiology
Synapse-specific molecules involved in the maturation of excitatory and inhibitory synapses. The basic organizing principles of synapse maturation are shared by excitatory and inhibitory synapses and include modifications in (1) scaffold proteins, (2) type, composition and abundance of postsynaptic receptors, (3) pre-synaptic and post-synaptic cytoskeleton structure, (4) presynaptic active zone and consequent presynaptic release. Several synapse-specific proteins are recruited in each of these steps and contribute in unique ways to the maturation of different types of synapses.
+) oriens–lacunosum moleculare (O-LM) interneurons are strongly facilitating (low release probability) whereas synapses onto Elfn1-negative parvalbumin-positive (PV +) interneurons are depressing (high release probability) [53]. So far, we have discussed examples of molecules that generate synapse diversity. It is, however, important to mention that transcriptional and post-transcriptional events are key determinants of such molecular diversity. Transcription factors act as master regulators of most cellular processes and synapse development is no exception. For example, the activity-dependent transcription factor Npas4 activates distinct programs of late-response genes in different neurons to selectively regulate their excitatory or inhibitory inputs [54,55]. Alternative splicing (AS) is a post-transcriptional process that greatly increases molecular diversity. Several studies have demonstrated the critical role of AS for synapse development [56] but it was only recently that an RNA-binding protein was shown to selectively orchestrate a synapse typespecific splicing program [57]. This seminal study showed that the RNA-binding protein SLM2 is essential for the functional specification of excitatory synapses and www.sciencedirect.com
drives an alternative splicing program which specifically controls glutamatergic transmission and plasticity [57]. Finally, against this background, it is important to mention that (1) ubiquitous molecules have been shown to regulate the development of specific subtypes of synapses [58–61] and (2) cell type-specific molecules, such as the receptor tyrosine-protein kinase ErbB4, can control the development of both excitatory inputs and inhibitory outputs in particular interneuron subtypes [62–64]. This is, however, not surprising and is likely due to the existence of different protein isoforms and/or synapse-specific interactors.
Conclusions and perspectives The global picture drawn here highlights how molecular diversity critically contributes to synapse diversity. Synapse type-specific molecules are employed at all steps of synaptic development to accomplish the ultimate goal of specifying connectivity. From core synaptic organizers to transcription factors to proteins that regulate the clustering of transmitter receptors, they all orchestrate the masterpiece of synapse diversity. Different molecules or similar molecules with different structure and Current Opinion in Neurobiology 2018, 53:8–15
12 Developmental neuroscience
Figure 3
Synapse formation
Synapse maturation
Excitatory synapses
F-actin
Elfn1
X, Y?
AMPAR BCAN
ErbB4 NPTX2 AMPAR Erbin
PSD95
Interneuron
NMDAR
Interneuron Current Opinion in Neurobiology
Distinctive molecular composition contributes to the specific development of excitatory synapses onto interneurons. Most subtypes of interneurons have few or no spine and excitatory synapses are made onto their soma or dendritic shafts. Consistent with these fundamental differences, specific molecules regulate the maturation of excitatory synapses onto interneurons but not onto pyramidal neurons. Synaptic organizers that specifically induce excitatory synapse assembly onto interneurons are likely to exist but have yet to be described. Note that some of the proteins shown here act in a cell type-specific manner, for example BCAN and NPTX2 regulate excitatory synapse maturation onto PV+ interneurons. Similarly, Elfn1 selectively modulates presynaptic release properties of excitatory synapses made onto a specific subgroup of SST+ inhibitory neurons but not onto PV+ cells.
interactors connect specific presynaptic and postsynaptic cells, control exactly where and when to form which type of synapses, and even what functional properties these synapses have. It is, however, of primary importance to emphasize that these ‘final connectivity patterns’ are nothing more than a modeling clay whose shaping extends into the entire postnatal life and is regulated by experience. Exactly like how molecular codes ensure axon target selection before synapse development, cell-specific or synapse type-specific programs also may function during experience-dependent synaptic plasticity and typically play key roles in processes like learning and memory [65–68]. Noteworthy, the very same molecules that contribute to synaptic diversity during development can be re-used in a cell-specific manner in the adult. One example is how the perineuronal net protein Brevican regulates the development of excitatory but not inhibitory inputs to PV+ interneurons as well as their remodeling during experience-dependent plasticity [48]. In this framework, we should emphasize that — besides the simplistic dichotomy between excitatory and inhibitory synapses — molecular diversity also contributes to synapse diversity within each of these classes. For instance, excitatory synapses exhibit fundamental differences depending on whether they are made onto glutamatergic or GABAergic neurons [69,70]. Consistently, several molecules (including the abovementioned Current Opinion in Neurobiology 2018, 53:8–15
Brevican and ErbB4) have been shown to specifically regulate excitatory synapse development onto interneurons but not onto pyramidal cells (Figure 3). Finally, it behooves us to point out that our knowledge of inhibitory synapse development has long lagged behind that of excitatory synapses. In recent years, considerable progress has been made towards understanding the molecular and structural components that distinguish mature inhibitory synapses [71,72]. The variety of inhibitory connections is arguably the quintessence of synapse diversity [73]. As such, it is surprising that the increase in our understanding of interneuron development and function was not accompanied by a parallel understanding of the molecules involved in the generation of the different types of synapses that they form. Do different developing interneurons already have distinct cohorts of molecular synaptic components? And, if so, how does this molecular diversity contribute to the encoding of synaptic diversity and wiring specificity? These are pressing questions whose answers will help to further understand how the precision of the synaptic circuitries is generated and how functional cortical networks are assembled.
Conflict of interest statement Nothing declared.
Acknowledgements We apologize to colleagues whose work is not cited in this review. Regrettably, space was too limited to cite all significant original articles. www.sciencedirect.com
Cortical excitatory and inhibitory synapse formation Favuzzi and Rico 13
Work in the B.R. laboratory is supported by grants from European Research Council (ERC-2012-StG 310021) and Wellcome Trust (202758/Z/16/Z). E. F. was supported by JAE-Pre 2011 fellowship (CSIC) and King’s College London funds and is currently supported by a NIMH-BRAIN Initiative grant (1R01MH111529-01). B.R. is a Wellcome Trust investigator.
References and recommended reading Papers of particular interest, published within the period of review, have been highlighted as: of special interest of outstanding interest 1.
Harris KD, Shepherd GMG: The neocortical circuit: themes and variations. Nat Neurosci 2015, 18:170-181.
2.
de Wit J, Ghosh A: Control of neural circuit formation by leucine-rich repeat proteins. Trends Neurosci 2014, 37:539-550.
3.
Takeichi M: The cadherin superfamily in neuronal connections and interactions. Nat Rev Neurosci 2007, 8:11-20.
4.
Tran TS, Rubio ME, Clem RL, Johnson D, Case L, TessierLavigne M, Huganir RL, Ginty DD, Kolodkin AL: Secreted semaphorins control spine distribution and morphogenesis in the postnatal CNS. Nature 2009, 462:1065-1069.
5.
Berns DS, DeNardo LA, Pederick DT, Luo L: Teneurin-3 controls topographic circuit assembly in the hippocampus. Nature 2018 http://dx.doi.org/10.1038/nature25463. This study uncovers a novel molecular mechanism that governs a precise topographic wiring. Teneurin-3 promotes homophilic adhesion in a splicing isoform-dependent manner and its spatially controlled expression mediates the assembly of a specific circuit in hippocampus.
6.
Anderson GR, Maxeiner S, Sando R, Tsetsenis T, Malenka RC, Su¨dhof TC: Postsynaptic adhesion GPCR latrophilin-2 mediates target recognition in entorhinal-hippocampal synapse assembly. J Cell Biol 2017, 216:3831-3846.
7.
Wang Y, Toledo-Rodriguez M, Gupta A, Wu C, Silberberg G, Luo J, Markram H: Anatomical, physiological and molecular properties of Martinotti cells in the somatosensory cortex of the juvenile rat. J Physiol (Lond) 2004, 561:65-90.
8.
Ango F, di Cristo G, Higashiyama H, Bennett V, Wu P, Huang ZJ: Ankyrin-based subcellular gradient of neurofascin, an immunoglobulin family protein, directs GABAergic innervation at purkinje axon initial segment. Cell 2004, 119:257-272.
9.
Siddiqui TJ, Craig AM: Synaptic organizing complexes. Curr Opin Neurobiol 2011, 21:132-143.
10. Scheiffele P, Fan J, Choih J, Fetter R, Serafini T: Neuroligin expressed in nonneuronal cells triggers presynaptic development in contacting axons. Cell 2000, 101:657-669. 11. Biederer T, Sara Y, Mozhayeva M, Atasoy D, Liu X, Kavalali ET, Su¨dhof TC: SynCAM, a synaptic adhesion molecule that drives synapse assembly. Science 2002, 297:1525-1531. 12. Chen LY, Jiang M, Zhang B, Gokce O, Su¨dhof TC: Conditional deletion of all neurexins defines diversity of essential synaptic organizer functions for neurexins. Neuron 2017, 94 611–625.e4. 13. Fuccillo MV, Fo¨ldy C, Go¨kce O¨, Rothwell PE, Sun GL, Malenka RC, Su¨dhof TC: Single-cell mRNA profiling reveals cell-typespecific expression of neurexin isoforms. Neuron 2015, 87:326340.
17. de Wit J, Sylwestrak E, O’Sullivan ML, Otto S, Tiglio K, Savas JN, Yates JR, Comoletti D, Taylor P, Ghosh A: LRRTM2 interacts with Neurexin1 and regulates excitatory synapse formation. Neuron 2009, 64:799-806. 18. Takahashi H, Arstikaitis P, Prasad T, Bartlett TE, Wang YT, Murphy TH, Craig AM: Postsynaptic TrkC and presynaptic PTPs function as a bidirectional excitatory synaptic organizing complex. Neuron 2011, 69:287-303. 19. Woo J, Kwon S-K, Choi S, Kim S, Lee J-R, Dunah AW, Sheng M, Kim E: Trans-synaptic adhesion between NGL-3 and LAR regulates the formation of excitatory synapses. Nat Neurosci 2009, 12:428-437. 20. de Wit J, O’Sullivan ML, Savas JN, Condomitti G, Caccese MC, Vennekens KM, Yates JR, Ghosh A: Unbiased discovery of glypican as a receptor for LRRTM4 in regulating excitatory synapse development. Neuron 2013, 79:696-711. 21. Siddiqui TJ, Tari PK, Connor SA, Zhang P, Dobie FA, She K, Kawabe H, Wang YT, Brose N, Craig AM: An LRRTM4-HSPG complex mediates excitatory synapse development on dentate gyrus granule cells. Neuron 2013, 79:680-695. 22. Takahashi H, Katayama K-I, Sohya K, Miyamoto H, Prasad T, Matsumoto Y, Ota M, Yasuda H, Tsumoto T, Aruga J et al.: Selective control of inhibitory synapse development by Slitrk3-PTPd trans-synaptic interaction. Nat Neurosci 2012, 15:389-398 S1. 23. Kuzirian MS, Moore AR, Staudenmaier EK, Friedel RH, Paradis S: The class 4 semaphorin Sema4D promotes the rapid assembly of GABAergic synapses in rodent hippocampus. J Neurosci 2013, 33:8961-8973. 24. Tanabe Y, Naito Y, Vasuta C, Lee AK, Soumounou Y, Linhoff MW, Takahashi H: IgSF21 promotes differentiation of inhibitory synapses via binding to neurexin2a. Nat Commun 2017, 8:408. This paper reveals IgSF21 as a new synaptogenic membrane protein that induces inhibitory, but not excitatory, presynaptic differentiation. The authors show that IgSF21 interacts with presynaptic NRX2 a and that IgSF21 knock-out mice exhibit reduced GABA-mediated synaptic transmission in hippocampal CA1 neurons but normal excitatory transmission. 25. Li J, Han W, Pelkey KA, Duan J, Mao X, Wang Y-X, Craig MT, Dong L, Petralia RS, McBain CJ et al.: Molecular dissection of neuroligin 2 and slitrk3 reveals an essential framework for gabaergic synapse development. Neuron 2017, 96 808–826.e8. 26. Frias CP, Bresser T, Scheefhals L, Hu HY, van Bergen en Henegouwen PMP, Hoogenraad CC, Wierenga CJ: Molecular pathway underlying bouton stabilization by Semaphorin4D during inhibitory synapse formation. BioRxiv 2018 http://dx.doi. org/10.1101/100271. 27. Matsuda K, Budisantoso T, Mitakidis N, Sugaya Y, Miura E, Kakegawa W, Yamasaki M, Konno K, Uchigashima M, Abe M et al.: Transsynaptic modulation of kainate receptor functions by C1q-like proteins. Neuron 2016, 90:752-767. 28. Matsuda K, Miura E, Miyazaki T, Kakegawa W, Emi K, Narumi S, Fukazawa Y, Ito-Ishida A, Kondo T, Shigemoto R et al.: Cbln1 is a ligand for an orphan glutamate receptor delta2, a bidirectional synapse organizer. Science 2010, 328:363-368. 29. Umemori H, Linhoff MW, Ornitz DM, Sanes JR: FGF22 and its close relatives are presynaptic organizing molecules in the mammalian brain. Cell 2004, 118:257-270.
14. Nguyen T-M, Schreiner D, Xiao L, Traunmu¨ller L, Bornmann C, Scheiffele P: An alternative splicing switch shapes neurexin repertoires in principal neurons versus interneurons in the mouse hippocampus. elife 2016, 5.
30. Terauchi A, Johnson-Venkatesh EM, Toth AB, Javed D, Sutton MA, Umemori H: Distinct FGFs promote differentiation of excitatory and inhibitory synapses. Nature 2010, 465:783-787.
15. Chih B, Gollan L, Scheiffele P: Alternative splicing controls selective trans-synaptic interactions of the neuroliginneurexin complex. Neuron 2006, 51:171-178.
31. Williams ME, Wilke SA, Daggett A, Davis E, Otto S, Ravi D, Ripley B, Bushong EA, Ellisman MH, Klein G et al.: Cadherin-9 regulates synapse-specific differentiation in the developing hippocampus. Neuron 2011, 71:640-655.
16. Poulopoulos A, Aramuni G, Meyer G, Soykan T, Hoon M, Papadopoulos T, Zhang M, Paarmann I, Fuchs C, Harvey K et al.: Neuroligin 2 drives postsynaptic assembly at perisomatic inhibitory synapses through gephyrin and collybistin. Neuron 2009, 63:628-642. www.sciencedirect.com
32. Sigler A, Oh WC, Imig C, Altas B, Kawabe H, Cooper BH, Kwon HB, Rhee J-S, Brose N: Formation and maintenance of functional spines in the absence of presynaptic glutamate release. Neuron 2017, 94 304–311.e4. Current Opinion in Neurobiology 2018, 53:8–15
14 Developmental neuroscience
33. Sando R, Bushong E, Zhu Y, Huang M, Considine C, Phan S, Ju S, Uytiepo M, Ellisman M, Maximov A: Assembly of excitatory synapses in the absence of glutamatergic neurotransmission. Neuron 2017, 94 312–321.e3. 34. Verhage M, Maia AS, Plomp JJ, Brussaard AB, Heeroma JH, Vermeer H, Toonen RF, Hammer RE, van den Berg TK, Missler M et al.: Synaptic assembly of the brain in the absence of neurotransmitter secretion. Science 2000, 287:864-869. 35. Katz LC, Shatz CJ: Synaptic activity and the construction of cortical circuits. Science 1996, 274:1133-1138. 36. Kim E, Sheng M: PDZ domain proteins of synapses. Nat Rev Neurosci 2004, 5:771-781. 37. El-Husseini AE, Schnell E, Chetkovich DM, Nicoll RA, Bredt DS: PSD-95 involvement in maturation of excitatory synapses. Science 2000, 290:1364-1368. 38. Ehrlich I, Klein M, Rumpel S, Malinow R: PSD-95 is required for activity-driven synapse stabilization. Proc Natl Acad Sci U S A 2007, 104:4176-4181. 39. Tyagarajan SK, Fritschy J-M: Gephyrin: a master regulator of neuronal function? Nat Rev Neurosci 2014, 15:141-156. 40. Matt L, Kim K, Hergarden AE, Patriarchi T, Malik ZA, Park DK, Chowdhury D, Buonarati OR, Henderson PB, Go¨kc¸ek Sarac¸ C¸ et al.: a-Actinin anchors PSD-95 at postsynaptic sites. Neuron 2018 http://dx.doi.org/10.1016/j.neuron.2018.01.036. 41. Boyken J, Grønborg M, Riedel D, Urlaub H, Jahn R, Chua JJE: Molecular profiling of synaptic vesicle docking sites reveals novel proteins but few differences between glutamatergic and GABAergic synapses. Neuron 2013, 78:285-297. 42. Toth AB, Terauchi A, Zhang LY, Johnson-Venkatesh EM, Larsen DJ, Sutton MA, Umemori H: Synapse maturation by activity-dependent ectodomain shedding of SIRPa. Nat Neurosci 2013, 16:1417-1425. 43. Kaeser PS, Deng L, Cha´vez AE, Liu X, Castillo PE, Su¨dhof TC: ELKS2alpha/CAST deletion selectively increases neurotransmitter release at inhibitory synapses. Neuron 2009, 64:227-239. 44. Hanse E, Seth H, Riebe I: AMPA-silent synapses in brain development and pathology. Nat Rev Neurosci 2013, 14:839-850. 45. Ko J, Kim S, Chung HS, Kim K, Han K, Kim H, Jun H, Kaang B-K, Kim E: SALM synaptic cell adhesion-like molecules regulate the differentiation of excitatory synapses. Neuron 2006, 50:233-245. 46. Kalashnikova E, Lorca RA, Kaur I, Barisone GA, Li B, Ishimaru T, Trimmer JS, Mohapatra DP, Dı´az E: SynDIG1: an activityregulated, AMPA-receptor-interacting transmembrane protein that regulates excitatory synapse development. Neuron 2010, 65:80-93. 47. Pelkey KA, Barksdale E, Craig MT, Yuan X, Sukumaran M, Vargish GA, Mitchell RM, Wyeth MS, Petralia RS, Chittajallu R et al.: Pentraxins coordinate excitatory synapse maturation and circuit integration of parvalbumin interneurons. Neuron 2015, 85:1257-1272. 48. Favuzzi E, Marques-Smith A, Deogracias R, Winterflood CM, Sa´nchez-Aguilera A, Mantoan L, Maeso P, Fernandes C, Ewers H, Rico B: Activity-dependent gating of parvalbumin interneuron function by the perineuronal net protein Brevican. Neuron 2017, 95 639–655.e10. This paper reveals a cell-specific molecular program through which a perineuronal net protein regulates the excitatory but not inhibitory inputs selectively onto PV+ interneurons both during development and upon experience-dependent plasticity. 49. Tao Y, Chen Y-J, Shen C, Luo Z, Bates CR, Lee D, Marchetto S, Gao T-M, Borg J-P, Xiong W-C et al.: Erbin interacts with TARP g-2 for surface expression of AMPA receptors in cortical interneurons. Nat Neurosci 2013, 16:290-299. 50. Jang S, Oh D, Lee Y, Hosy E, Shin H, van Riesen C, Whitcomb D, Warburton JM, Jo J, Kim D et al.: Synaptic adhesion molecule Current Opinion in Neurobiology 2018, 53:8–15
IgSF11 regulates synaptic transmission and plasticity. Nat Neurosci 2016, 19:84-93. 51. Ge Y, Kang Y, Cassidy RM, Moon K-M, Lewis R, Wong ROL, Foster LJ, Craig AM: Clptm1 limits forward trafficking of GABAA receptors to scale inhibitory synaptic strength. Neuron 2018, 97 596–610.e8. 52. Yamasaki T, Hoyos-Ramirez E, Martenson JS, Morimoto Tomita M, Tomita S: GARLH family proteins stabilize GABAA receptors at synapses. Neuron 2017, 93 1138–1152.e6. This paper pushes forward our understanding of the molecular composition of inhibitory postsynapses. The authors show that transmembrane GARLH family proteins form a tripartite complex with GABAARs and NL2 and that disrupting GARLH expression reduces the synaptic localization of the g g2-containing GABAARs and GABAAR-mediated synaptic transmission. 53. Sylwestrak EL, Ghosh A: Elfn1 regulates target-specific release probability at CA1-interneuron synapses. Science 2012, 338:536-540. This paper shows that functional synapse diversity can be triggered at the presynaptic release site depending on the expression of the LRR protein Elfn1 from the postsynaptic target. Using a combination of knockdown and overexpression techniques, the authors show that synapses made by pyramidal cell axons onto a subgroup of SST+ cells are strongly facilitating as a result of Elfn1 function, whereas those made onto PV+ cells, that do not express Elfn1, are depressing. 54. Spiegel I, Mardinly AR, Gabel HW, Bazinet JE, Couch CH, Tzeng CP, Harmin DA, Greenberg ME: Npas4 regulates excitatory-inhibitory balance within neural circuits through cell-type-specific gene programs. Cell 2014, 157:1216-1229. This paper shows that neuronal activity induces expression of Npas4 in both excitatory and inhibitory neurons. The late-response genes induced in the two cell types are, however, very different: they promote inhibition onto excitatory neurons while inducing excitation onto SST+ inhibitory neurons. This combined regulation facilitates a precise circuit response to sensory experience. 55. Lin Y, Bloodgood BL, Hauser JL, Lapan AD, Koon AC, Kim T-K, Hu LS, Malik AN, Greenberg ME: Activity-dependent regulation of inhibitory synapse development by Npas4. Nature 2008, 455:1198-1204. 56. Vuong CK, Black DL, Zheng S: The neurogenetics of alternative splicing. Nat Rev Neurosci 2016, 17:265-281. 57. Traunmu¨ller L, Gomez AM, Nguyen T-M, Scheiffele P: Control of neuronal synapse specification by a highly dedicated alternative splicing program. Science 2016, 352:982-986. This paper demonstrates that a synapse type-specific splicing program orchestrates neuronal synapse specification. Deletion of the RNA-binding protein SLM2 selectively impacts glutamatergic transmission and plasticity by affecting only few transcripts which were critically involved in excitatory synapse development. The structural, functional and behavioral deficits of SLM2 KO mice could be rescued by restoration of a single SLM2-dependent target exon in the synaptic recognition molecule neurexin-1. 58. Berryer MH, Chattopadhyaya B, Xing P, Riebe I, Bosoi C, Sanon N, Antoine-Bertrand J, Le´vesque M, Avoli M, Hamdan FF et al.: Decrease of SYNGAP1 in GABAergic cells impairs inhibitory synapse connectivity, synaptic inhibition and cognitive function. Nat Commun 2016, 7:13340. 59. Chattopadhyaya B, Baho E, Huang ZJ, Schachner M, Di Cristo G: Neural cell adhesion molecule-mediated Fyn activation promotes GABAergic synapse maturation in postnatal mouse cortex. J Neurosci 2013, 33:5957-5968. 60. Tai Y, Janas JA, Wang C-L, Van Aelst L: Regulation of chandelier cell cartridge and bouton development via DOCK7-mediated ErbB4 activation. Cell Rep 2014, 6:254-263. 61. Fossati M, Pizzarelli R, Schmidt ER, Kupferman JV, Stroebel D, Polleux F, Charrier C: SRGAP2 and its human-specific paralog co-regulate the development of excitatory and inhibitory synapses. Neuron 2016, 91:356-369. 62. Del Pino I, Brotons-Mas JR, Marques-Smith A, Marighetto A, Frick A, Marı´n O, Rico B: Abnormal wiring of CCK+ basket cells disrupts spatial information coding. Nat Neurosci 2017, 20:784-792. www.sciencedirect.com
Cortical excitatory and inhibitory synapse formation Favuzzi and Rico 15
63. Del Pino I, Garcı´a-Frigola C, Dehorter N, Brotons-Mas JR, AlvarezSalvado E, Martı´nez de Lagra´n M, Ciceri G, Gabaldo´n MV, Moratal D, Dierssen M et al.: Erbb4 deletion from fast-spiking interneurons causes schizophrenia-like phenotypes. Neuron 2013, 79:1152-1168. 64. Ting AK, Chen Y, Wen L, Yin D-M, Shen C, Tao Y, Liu X, Xiong W-C, Mei L: Neuregulin 1 promotes excitatory synapse development and function in GABAergic interneurons. J Neurosci 2011, 31:15-25.
68. Mardinly AR, Spiegel I, Patrizi A, Centofante E, Bazinet JE, Tzeng CP, Mandel-Brehm C, Harmin DA, Adesnik H, Fagiolini M et al.: Sensory experience regulates cortical inhibition by inducing IGF1 in VIP neurons. Nature 2016, 531:371-375. 69. Gulya´s AI, Megı´as M, Emri Z, Freund TF: Total number and ratio of excitatory and inhibitory synapses converging onto single interneurons of different types in the CA1 area of the rat hippocampus. J Neurosci 1999, 19:10082-10097. 70. Spruston N: Pyramidal neurons: dendritic structure and synaptic integration. Nat Rev Neurosci 2008, 9:206-221.
65. Weng F-J, Garcia RI, Lutzu S, Alvin˜a K, Zhang Y, Dushko M, Ku T, Zemoura K, Rich D, Garcia-Dominguez D et al.: Npas4 is a critical regulator of learning-induced plasticity at mossy fiber-CA3 synapses during contextual memory formation. Neuron 2018 http://dx.doi.org/10.1016/j.neuron.2018.01.026.
71. Fritschy J-M, Panzanelli P, Tyagarajan SK: Molecular and functional heterogeneity of GABAergic synapses. Cell Mol Life Sci 2012, 69:2485-2499.
66. Lisman J, Cooper K, Sehgal M, Silva AJ: Memory formation depends on both synapse-specific modifications of synaptic strength and cell-specific increases in excitability. Nat Neurosci 2018 http://dx.doi.org/10.1038/s41593-018-0076-6.
72. Paul A, Crow M, Raudales R, He M, Gillis J, Huang ZJ: Transcriptional architecture of synaptic communication delineates gabaergic neuron identity. Cell 2017, 171 522–539. e20.
67. Bloodgood BL, Sharma N, Browne HA, Trepman AZ, Greenberg ME: The activity-dependent transcription factor NPAS4 regulates domain-specific inhibition. Nature 2013, 503:121-125.
73. Tremblay R, Lee S, Rudy B: Gabaergic interneurons in the neocortex: from cellular properties to circuits. Neuron 2016, 91:260-292.
www.sciencedirect.com
Current Opinion in Neurobiology 2018, 53:8–15
ScienceDirect Molecular diversity underlying cortical excitatory and inhibitory synapse development Emilia Favuzzi1,2,3 and Beatriz Rico1,2 The complexity and precision of cortical circuitries is achieved during development due to the exquisite diversity of synapse types that is generated in a highly regulated manner. Here, we review the recent increase in our understanding of how synapse type-specific molecules differentially regulate the development of excitatory and inhibitory synapses. Moreover, several synapse subtype-specific molecules have been shown to control the targeting, formation or maturation of particular subtypes of excitatory synapses. Because inhibitory neurons are extremely diverse, a similar molecular diversity is likely to underlie the development of different inhibitory synapses making it a promising topic for future investigation in the field of the synapse development.
Addresses 1 Centre for Developmental Neurobiology, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London SE1 1UL, United Kingdom 2 MRC Centre for Neurodevelopmental Disorders, King’s College London, London SE1 1UL, United Kingdom Corresponding author: Present address: Broad Institute, Stanley Center for Psychiatric Research, Cambridge, MA 02142 and Harvard Medical School, Department of Neurobiology, Boston, MA 02115, USA.
3
types which fall in two broad categories: excitatory pyramidal neurons and inhibitory GABAergic interneurons. The elaborate but partially stereotyped connectivity patterns of different neuronal types are perfectly suited to fulfill specific functional roles and underlie the cortex’s unique computational prowess [1]. Such specificity implies not only cellular but also synaptic diversity that is built upon molecular diversity and emerges through a tightly regulated sequence of developmental processes. Each of these steps gradually restricts the number of potential synaptic partners and further sculpts specific synaptic properties. Regardless of its multiplicity, it is generally agreed that synapse development involves two broad sequential phases. First, mostly genetically determined processes lead to a transient and relatively nonspecific contact that is stabilized by molecular interactions. Afterward, during synapse maturation, a series of progressively more activity-dependent processes kick in. In this review, we will focus on the developmental molecular mechanisms that generate synapse diversity in the cerebral cortex, with a particular emphasis on the differences and similarities existing between excitatory and inhibitory synapses.
Current Opinion in Neurobiology 2018, 53:8–15 This review comes from a themed issue on Developmental neuroscience Edited by Alex Kolodkin and Guillermina Lo´pez-Bendito
https://doi.org/10.1016/j.conb.2018.03.011 0959-4388/ã 2018 Elsevier Ltd. All rights reserved.
Introduction From both an evolutionary and a developmental perspective, brain wiring reaches an exceptional level of complexity in the cerebral cortex. The precision that characterizes this process is truly astonishing and even more so if one considers its outcome, us. Cortical circuitries, honed over hundreds of million years of evolution, are composed of an interconnected multitude of neuronal cell 4
4. Title freely adapted from Oscar Wilde’s 1895 play ‘The Importance of Being Earnest’. The importance of being Axon4: first contact between synaptic partners Axons terminals are endowed with the ability to discriminate their correct synaptic targets among a dense array of potential partners. A key role in mediating the first contact between synaptic partners is played by transmembrane cell adhesion molecules (CAMs) that serve both as permissive adhesion substrates and as recognition tags. For example, distinct cadherins and leucine-rich repeat (LRR) proteins are expressed in different cell types and can regulate input-specific target selection [2,3]. Classical guidance cues like Semaphorins and their receptor neuropilins have been associated with proximal and distal pyramidal cell dendritic targeting [4]. In addition, recent work showed that the cell-adhesion G protein-coupled receptor of alpha-latrotoxin latrophilin-1 and the transmembrane protein teneurin-3 are required for the specific targeting of entorhinal cortex afferents to CA1 pyramidal dendrites and CA1 hippocampal axons to distal subiculum, respectively [5,6].
Title freely adapted from Oscar Wilde’s 1895 play ‘The Importance of Being Earnest’.
Current Opinion in Neurobiology 2018, 53:8–15
www.sciencedirect.com
Cortical excitatory and inhibitory synapse formation Favuzzi and Rico 9
Cortical inhibitory neurons also exhibit exquisite target specificity. A classic example is represented by SSTpositive Martinotti cells, which are particularly abundant in neocortical layer V and possess ascending axons that arborize in layer I where they establish synapses onto the dendritic tufts of pyramidal neurons [7]. In the cerebellum, chemoaffinity-based recognition strategies ensure the correct targeting of inhibitory axons [8]. Although it is possible that similar mechanisms function across different cortices, the molecules regulating inhibitory target specificity in the cerebral cortex still await discovery.
5. Title freely adapted from Oscar Wilde’s 1895 play ‘An Ideal Husband’.An Ideal Husband, Act I5: forming a synapse Once matching synaptic partners are in contact, a coordinated assembly of molecules on both sides of the synapse takes place. This is mediated by synaptic organizers which, in addition to having a cohesive role, initiate bidirectional trans-synaptic signaling events that trigger a near-complete program for pre-synaptic and post-synaptic differentiation [9]. The best example of cell adhesion molecules with both adhesive and inducing function at synapses are neuroligins and neurexins [10]. The elegant experiment that led to the discovery of the neuroligins and neurexins as potent inducers of synapse formation has become a ‘classic’ of neuroscience and paved the way for the discovery of several other synaptogenic adhesion complexes, such as the cell adhesion molecule SynCAM [11] or members of the leucine-rich repeat (LRR) family of cell adhesion proteins [2]. Although most synaptic organizers are ubiquitously expressed, the exceptional diversity of isoforms, ligands and interactors that they can combine in a cell-specific or circuit-specific manner critically contributes to generating synapse diversity (Figure 1). For instance, different neurexin isoforms exhibit a cell-type specific expression and pan-neurexin deletion produces dramatically diverse phenotypes at different types of synapses [12–14]. Another example is provided by how different neuroligin splice variants selectively induce glutamatergic or GABAergic presynaptic differentiation, likely through specific trans-synaptic interactions with Neurexins [15]. Selectivity may be further achieved by recruiting synapse type-specific molecules, as is the case for Neuroligin 2 which by interacting with Gephyrin recruits Gephyrin-associated proteins to inhibitory postsynapses [16]. In addition to ubiquitous synaptogenic complexes, several synapse type-specific organizers have also been identified. Although nearly all of them promote only 5
Title freely adapted from Oscar Wilde’s 1895 play ‘An Ideal Husband’. www.sciencedirect.com
excitatory synapse development [17–21], Sema4D-PlexinB1, Slitrk3-PTPd and Neurexin2a-IgSF21 were identified as trans-synaptic organizing complexes selectively required for GABAergic synapse development [22,23,24]. Interestingly, recent work showed that, despite having inducing properties, both Slitrk3 and Sema4D act in a second phase of synapse formation. In particular, Slitrk3 functions in a hierarchical and synergistic manner after Neuroligin 2 initiates the synaptic assembly [25] and Sema4D induces remodeling of the actin cytoskeleton and consequent bouton stabilization [26]. Similarly, C1q-like proteins belong to a family of extracellular synaptic organizers and have been recently shown to recruit functional postsynaptic kainate-type glutamate receptors complexes during synapse maturation (Figure 2) [27,28]. These recent findings suggest that the line traced between synapse formation and maturation is likely to be less clear-cut than what is often assumed for the sake of description. Most synaptogenic molecules discovered so far are transmembrane adhesion molecules. However, members of the fibroblast growth factor (FGF) family have been shown to act as soluble target-derived presynaptic organizers that induce clustering of synaptic vesicles and differentiation of the presynaptic specialization [29]. Interestingly, the synaptogenic function of FGFs is synapse type-specific: FGF22 and FGF7 promote the differentiation of excitatory and inhibitory presynaptic terminals, respectively [30]. In addition to synaptic organizers, cell type-specific molecules that have adhesive but not inducing properties also contribute to synapse specificity by dictating whether a transient contact is transformed in a synapse or not. An excellent example of this selective synaptogenesis onto correct targets is how cadherin-9 regulates preferential synapse formation — rather than axon targeting — of dentate gyrus (DG) axons onto CA3 but not CA1 pyramidal neurons in the hippocampus [31].
An Ideal Husband, Act II: synapse maturation Excitatory and inhibitory synapses are constantly generated at a high rate in the developing cortex. Newborn synapses are functional but immature. Subsequently, a combination of genetically predetermined developmental programs [32–34] and activity-dependent processes mediates synapse maturation [35]. The maturation of a synapse involves structural and functional changes that are intimately related to both an increased efficacy of presynaptic neurotransmitter release and a mature profile of postsynaptic receptors. The basic organizing principles of synapse maturation hold true for both excitatory and inhibitory synapses (Figure 2). A critical step in this process is the recruitment of scaffolding proteins, abundant and essential Current Opinion in Neurobiology 2018, 53:8–15
10 Developmental neuroscience
Figure 1
Synapse formation Excitatory synapses
Inhibitory synapses
Cdh9 HSPG NRX1β4(–) LAR Glypican PTPσ LRRTM4 FGF22
Slitrk2
NRX1β4(+) PLXNB1 PTPδ NRX2α NRX1α4(–)
NGL-3 NL1BTrkC LRRTM2 FGF7
Pyramidal cell
NL2A NL2A Slitrk3 IgSF21 Sema4D
Current Opinion in Neurobiology
Molecular diversity supports the formation of excitatory and inhibitory synapses. Synapse-type specific organizers, adhesion molecules and targetderived soluble factors generate the very first differences between excitatory and inhibitory synapses during their formation. Due to their high number, not all molecules specifically involved in the formation of excitatory synapses are shown. Note also that proteins that regulate the formation of both excitatory and inhibitory synapses have been excluded from the schematic.
components of the postsynaptic specialization [36]. Scaffold proteins anchor neurotransmitter receptors and adhesion molecules and link them with downstream signaling proteins. At the excitatory synapses, such scaffold proteins include the membrane-associated guanylate kinases (MAGUKs), among which prominent in synapse maturation is the role of PSD95 [37,38]. Likewise, the scaffold protein gephyrin and several gephyrin-associated proteins are recruited to the inhibitory synapses [39]. Another structural element that undergoes profound remodeling on both sides of the maturing excitatory as well as inhibitory synapses is the cytoskeleton. Recent work showed that the F-actin binding protein a-actinin anchors PSD-95 at the excitatory postsynapse [40]. In contrast, the exact molecular mechanisms by which gephyrin is targeted and clustered to inhibitory synapses are not well understood [39]. Presynaptically, the cytoskeletal structure supports the organization of the active zone which displays some degree of molecular heterogeneity at different types of synapses [26,41–43]. Synapse maturation also involves the incorporation of clusters of AMPA (for excitatory synapses) and GABAA (for inhibitory synapses) receptors. The importance of Current Opinion in Neurobiology 2018, 53:8–15
this step has been well studied for glutamatergic synapse maturation. Synaptic accumulation of AMPA receptors (AMPARs) leads to the simultaneous activation of NMDA receptors (NMDARs) and to the potentiation of immature synapses [44]. Most molecules that selectively regulate excitatory synapse maturation play a role precisely in the clustering, trafficking or synaptic delivery of AMPARs, further underscoring its prominence [45–47,48,49,50]. Although less studied, regulation of GABAA receptor (GABAAR) trafficking has been shown to modulate inhibitory synaptic strength in a relatively similar way. In fact, two recently discovered molecules, GARLH family proteins and Clptm1, involved in controlling the trafficking and synaptic localization of GABAARs, respectively, critically regulate inhibitory synaptic transmission [51,52]. Another aspect of synapse maturation in which cell typeselective proteins contribute to synapse diversity is the determination of synaptic properties. One excellent — and to our knowledge still unique — example is the target-induced differences in presynaptic release properties of CA1 pyramidal cell excitatory synapses. As a result of the postsynaptic expression of the LRR protein Elfn1, synapses made onto somatostatin-positive (SST www.sciencedirect.com
Cortical excitatory and inhibitory synapse formation Favuzzi and Rico 11
Figure 2
Synapse maturation Excitatory synapses
Inhibitory synapses F-actin SIRPα LGI1 AMPAR
SynDIG1 AMPAR SALM2 PSD95 ADAM22 α-actinin IgSF11
NRX3β4+SS525b C1qI2/3 KAR
F-actin
MET
NMDAR PlexinB1 Sema4D
ErbB4 GABA R
Gephyrin
Pyramidal cell
Clptm1
F-actin GARLH Current Opinion in Neurobiology
Synapse-specific molecules involved in the maturation of excitatory and inhibitory synapses. The basic organizing principles of synapse maturation are shared by excitatory and inhibitory synapses and include modifications in (1) scaffold proteins, (2) type, composition and abundance of postsynaptic receptors, (3) pre-synaptic and post-synaptic cytoskeleton structure, (4) presynaptic active zone and consequent presynaptic release. Several synapse-specific proteins are recruited in each of these steps and contribute in unique ways to the maturation of different types of synapses.
+) oriens–lacunosum moleculare (O-LM) interneurons are strongly facilitating (low release probability) whereas synapses onto Elfn1-negative parvalbumin-positive (PV +) interneurons are depressing (high release probability) [53]. So far, we have discussed examples of molecules that generate synapse diversity. It is, however, important to mention that transcriptional and post-transcriptional events are key determinants of such molecular diversity. Transcription factors act as master regulators of most cellular processes and synapse development is no exception. For example, the activity-dependent transcription factor Npas4 activates distinct programs of late-response genes in different neurons to selectively regulate their excitatory or inhibitory inputs [54,55]. Alternative splicing (AS) is a post-transcriptional process that greatly increases molecular diversity. Several studies have demonstrated the critical role of AS for synapse development [56] but it was only recently that an RNA-binding protein was shown to selectively orchestrate a synapse typespecific splicing program [57]. This seminal study showed that the RNA-binding protein SLM2 is essential for the functional specification of excitatory synapses and www.sciencedirect.com
drives an alternative splicing program which specifically controls glutamatergic transmission and plasticity [57]. Finally, against this background, it is important to mention that (1) ubiquitous molecules have been shown to regulate the development of specific subtypes of synapses [58–61] and (2) cell type-specific molecules, such as the receptor tyrosine-protein kinase ErbB4, can control the development of both excitatory inputs and inhibitory outputs in particular interneuron subtypes [62–64]. This is, however, not surprising and is likely due to the existence of different protein isoforms and/or synapse-specific interactors.
Conclusions and perspectives The global picture drawn here highlights how molecular diversity critically contributes to synapse diversity. Synapse type-specific molecules are employed at all steps of synaptic development to accomplish the ultimate goal of specifying connectivity. From core synaptic organizers to transcription factors to proteins that regulate the clustering of transmitter receptors, they all orchestrate the masterpiece of synapse diversity. Different molecules or similar molecules with different structure and Current Opinion in Neurobiology 2018, 53:8–15
12 Developmental neuroscience
Figure 3
Synapse formation
Synapse maturation
Excitatory synapses
F-actin
Elfn1
X, Y?
AMPAR BCAN
ErbB4 NPTX2 AMPAR Erbin
PSD95
Interneuron
NMDAR
Interneuron Current Opinion in Neurobiology
Distinctive molecular composition contributes to the specific development of excitatory synapses onto interneurons. Most subtypes of interneurons have few or no spine and excitatory synapses are made onto their soma or dendritic shafts. Consistent with these fundamental differences, specific molecules regulate the maturation of excitatory synapses onto interneurons but not onto pyramidal neurons. Synaptic organizers that specifically induce excitatory synapse assembly onto interneurons are likely to exist but have yet to be described. Note that some of the proteins shown here act in a cell type-specific manner, for example BCAN and NPTX2 regulate excitatory synapse maturation onto PV+ interneurons. Similarly, Elfn1 selectively modulates presynaptic release properties of excitatory synapses made onto a specific subgroup of SST+ inhibitory neurons but not onto PV+ cells.
interactors connect specific presynaptic and postsynaptic cells, control exactly where and when to form which type of synapses, and even what functional properties these synapses have. It is, however, of primary importance to emphasize that these ‘final connectivity patterns’ are nothing more than a modeling clay whose shaping extends into the entire postnatal life and is regulated by experience. Exactly like how molecular codes ensure axon target selection before synapse development, cell-specific or synapse type-specific programs also may function during experience-dependent synaptic plasticity and typically play key roles in processes like learning and memory [65–68]. Noteworthy, the very same molecules that contribute to synaptic diversity during development can be re-used in a cell-specific manner in the adult. One example is how the perineuronal net protein Brevican regulates the development of excitatory but not inhibitory inputs to PV+ interneurons as well as their remodeling during experience-dependent plasticity [48]. In this framework, we should emphasize that — besides the simplistic dichotomy between excitatory and inhibitory synapses — molecular diversity also contributes to synapse diversity within each of these classes. For instance, excitatory synapses exhibit fundamental differences depending on whether they are made onto glutamatergic or GABAergic neurons [69,70]. Consistently, several molecules (including the abovementioned Current Opinion in Neurobiology 2018, 53:8–15
Brevican and ErbB4) have been shown to specifically regulate excitatory synapse development onto interneurons but not onto pyramidal cells (Figure 3). Finally, it behooves us to point out that our knowledge of inhibitory synapse development has long lagged behind that of excitatory synapses. In recent years, considerable progress has been made towards understanding the molecular and structural components that distinguish mature inhibitory synapses [71,72]. The variety of inhibitory connections is arguably the quintessence of synapse diversity [73]. As such, it is surprising that the increase in our understanding of interneuron development and function was not accompanied by a parallel understanding of the molecules involved in the generation of the different types of synapses that they form. Do different developing interneurons already have distinct cohorts of molecular synaptic components? And, if so, how does this molecular diversity contribute to the encoding of synaptic diversity and wiring specificity? These are pressing questions whose answers will help to further understand how the precision of the synaptic circuitries is generated and how functional cortical networks are assembled.
Conflict of interest statement Nothing declared.
Acknowledgements We apologize to colleagues whose work is not cited in this review. Regrettably, space was too limited to cite all significant original articles. www.sciencedirect.com
Cortical excitatory and inhibitory synapse formation Favuzzi and Rico 13
Work in the B.R. laboratory is supported by grants from European Research Council (ERC-2012-StG 310021) and Wellcome Trust (202758/Z/16/Z). E. F. was supported by JAE-Pre 2011 fellowship (CSIC) and King’s College London funds and is currently supported by a NIMH-BRAIN Initiative grant (1R01MH111529-01). B.R. is a Wellcome Trust investigator.
References and recommended reading Papers of particular interest, published within the period of review, have been highlighted as: of special interest of outstanding interest 1.
Harris KD, Shepherd GMG: The neocortical circuit: themes and variations. Nat Neurosci 2015, 18:170-181.
2.
de Wit J, Ghosh A: Control of neural circuit formation by leucine-rich repeat proteins. Trends Neurosci 2014, 37:539-550.
3.
Takeichi M: The cadherin superfamily in neuronal connections and interactions. Nat Rev Neurosci 2007, 8:11-20.
4.
Tran TS, Rubio ME, Clem RL, Johnson D, Case L, TessierLavigne M, Huganir RL, Ginty DD, Kolodkin AL: Secreted semaphorins control spine distribution and morphogenesis in the postnatal CNS. Nature 2009, 462:1065-1069.
5.
Berns DS, DeNardo LA, Pederick DT, Luo L: Teneurin-3 controls topographic circuit assembly in the hippocampus. Nature 2018 http://dx.doi.org/10.1038/nature25463. This study uncovers a novel molecular mechanism that governs a precise topographic wiring. Teneurin-3 promotes homophilic adhesion in a splicing isoform-dependent manner and its spatially controlled expression mediates the assembly of a specific circuit in hippocampus.
6.
Anderson GR, Maxeiner S, Sando R, Tsetsenis T, Malenka RC, Su¨dhof TC: Postsynaptic adhesion GPCR latrophilin-2 mediates target recognition in entorhinal-hippocampal synapse assembly. J Cell Biol 2017, 216:3831-3846.
7.
Wang Y, Toledo-Rodriguez M, Gupta A, Wu C, Silberberg G, Luo J, Markram H: Anatomical, physiological and molecular properties of Martinotti cells in the somatosensory cortex of the juvenile rat. J Physiol (Lond) 2004, 561:65-90.
8.
Ango F, di Cristo G, Higashiyama H, Bennett V, Wu P, Huang ZJ: Ankyrin-based subcellular gradient of neurofascin, an immunoglobulin family protein, directs GABAergic innervation at purkinje axon initial segment. Cell 2004, 119:257-272.
9.
Siddiqui TJ, Craig AM: Synaptic organizing complexes. Curr Opin Neurobiol 2011, 21:132-143.
10. Scheiffele P, Fan J, Choih J, Fetter R, Serafini T: Neuroligin expressed in nonneuronal cells triggers presynaptic development in contacting axons. Cell 2000, 101:657-669. 11. Biederer T, Sara Y, Mozhayeva M, Atasoy D, Liu X, Kavalali ET, Su¨dhof TC: SynCAM, a synaptic adhesion molecule that drives synapse assembly. Science 2002, 297:1525-1531. 12. Chen LY, Jiang M, Zhang B, Gokce O, Su¨dhof TC: Conditional deletion of all neurexins defines diversity of essential synaptic organizer functions for neurexins. Neuron 2017, 94 611–625.e4. 13. Fuccillo MV, Fo¨ldy C, Go¨kce O¨, Rothwell PE, Sun GL, Malenka RC, Su¨dhof TC: Single-cell mRNA profiling reveals cell-typespecific expression of neurexin isoforms. Neuron 2015, 87:326340.
17. de Wit J, Sylwestrak E, O’Sullivan ML, Otto S, Tiglio K, Savas JN, Yates JR, Comoletti D, Taylor P, Ghosh A: LRRTM2 interacts with Neurexin1 and regulates excitatory synapse formation. Neuron 2009, 64:799-806. 18. Takahashi H, Arstikaitis P, Prasad T, Bartlett TE, Wang YT, Murphy TH, Craig AM: Postsynaptic TrkC and presynaptic PTPs function as a bidirectional excitatory synaptic organizing complex. Neuron 2011, 69:287-303. 19. Woo J, Kwon S-K, Choi S, Kim S, Lee J-R, Dunah AW, Sheng M, Kim E: Trans-synaptic adhesion between NGL-3 and LAR regulates the formation of excitatory synapses. Nat Neurosci 2009, 12:428-437. 20. de Wit J, O’Sullivan ML, Savas JN, Condomitti G, Caccese MC, Vennekens KM, Yates JR, Ghosh A: Unbiased discovery of glypican as a receptor for LRRTM4 in regulating excitatory synapse development. Neuron 2013, 79:696-711. 21. Siddiqui TJ, Tari PK, Connor SA, Zhang P, Dobie FA, She K, Kawabe H, Wang YT, Brose N, Craig AM: An LRRTM4-HSPG complex mediates excitatory synapse development on dentate gyrus granule cells. Neuron 2013, 79:680-695. 22. Takahashi H, Katayama K-I, Sohya K, Miyamoto H, Prasad T, Matsumoto Y, Ota M, Yasuda H, Tsumoto T, Aruga J et al.: Selective control of inhibitory synapse development by Slitrk3-PTPd trans-synaptic interaction. Nat Neurosci 2012, 15:389-398 S1. 23. Kuzirian MS, Moore AR, Staudenmaier EK, Friedel RH, Paradis S: The class 4 semaphorin Sema4D promotes the rapid assembly of GABAergic synapses in rodent hippocampus. J Neurosci 2013, 33:8961-8973. 24. Tanabe Y, Naito Y, Vasuta C, Lee AK, Soumounou Y, Linhoff MW, Takahashi H: IgSF21 promotes differentiation of inhibitory synapses via binding to neurexin2a. Nat Commun 2017, 8:408. This paper reveals IgSF21 as a new synaptogenic membrane protein that induces inhibitory, but not excitatory, presynaptic differentiation. The authors show that IgSF21 interacts with presynaptic NRX2 a and that IgSF21 knock-out mice exhibit reduced GABA-mediated synaptic transmission in hippocampal CA1 neurons but normal excitatory transmission. 25. Li J, Han W, Pelkey KA, Duan J, Mao X, Wang Y-X, Craig MT, Dong L, Petralia RS, McBain CJ et al.: Molecular dissection of neuroligin 2 and slitrk3 reveals an essential framework for gabaergic synapse development. Neuron 2017, 96 808–826.e8. 26. Frias CP, Bresser T, Scheefhals L, Hu HY, van Bergen en Henegouwen PMP, Hoogenraad CC, Wierenga CJ: Molecular pathway underlying bouton stabilization by Semaphorin4D during inhibitory synapse formation. BioRxiv 2018 http://dx.doi. org/10.1101/100271. 27. Matsuda K, Budisantoso T, Mitakidis N, Sugaya Y, Miura E, Kakegawa W, Yamasaki M, Konno K, Uchigashima M, Abe M et al.: Transsynaptic modulation of kainate receptor functions by C1q-like proteins. Neuron 2016, 90:752-767. 28. Matsuda K, Miura E, Miyazaki T, Kakegawa W, Emi K, Narumi S, Fukazawa Y, Ito-Ishida A, Kondo T, Shigemoto R et al.: Cbln1 is a ligand for an orphan glutamate receptor delta2, a bidirectional synapse organizer. Science 2010, 328:363-368. 29. Umemori H, Linhoff MW, Ornitz DM, Sanes JR: FGF22 and its close relatives are presynaptic organizing molecules in the mammalian brain. Cell 2004, 118:257-270.
14. Nguyen T-M, Schreiner D, Xiao L, Traunmu¨ller L, Bornmann C, Scheiffele P: An alternative splicing switch shapes neurexin repertoires in principal neurons versus interneurons in the mouse hippocampus. elife 2016, 5.
30. Terauchi A, Johnson-Venkatesh EM, Toth AB, Javed D, Sutton MA, Umemori H: Distinct FGFs promote differentiation of excitatory and inhibitory synapses. Nature 2010, 465:783-787.
15. Chih B, Gollan L, Scheiffele P: Alternative splicing controls selective trans-synaptic interactions of the neuroliginneurexin complex. Neuron 2006, 51:171-178.
31. Williams ME, Wilke SA, Daggett A, Davis E, Otto S, Ravi D, Ripley B, Bushong EA, Ellisman MH, Klein G et al.: Cadherin-9 regulates synapse-specific differentiation in the developing hippocampus. Neuron 2011, 71:640-655.
16. Poulopoulos A, Aramuni G, Meyer G, Soykan T, Hoon M, Papadopoulos T, Zhang M, Paarmann I, Fuchs C, Harvey K et al.: Neuroligin 2 drives postsynaptic assembly at perisomatic inhibitory synapses through gephyrin and collybistin. Neuron 2009, 63:628-642. www.sciencedirect.com
32. Sigler A, Oh WC, Imig C, Altas B, Kawabe H, Cooper BH, Kwon HB, Rhee J-S, Brose N: Formation and maintenance of functional spines in the absence of presynaptic glutamate release. Neuron 2017, 94 304–311.e4. Current Opinion in Neurobiology 2018, 53:8–15
14 Developmental neuroscience
33. Sando R, Bushong E, Zhu Y, Huang M, Considine C, Phan S, Ju S, Uytiepo M, Ellisman M, Maximov A: Assembly of excitatory synapses in the absence of glutamatergic neurotransmission. Neuron 2017, 94 312–321.e3. 34. Verhage M, Maia AS, Plomp JJ, Brussaard AB, Heeroma JH, Vermeer H, Toonen RF, Hammer RE, van den Berg TK, Missler M et al.: Synaptic assembly of the brain in the absence of neurotransmitter secretion. Science 2000, 287:864-869. 35. Katz LC, Shatz CJ: Synaptic activity and the construction of cortical circuits. Science 1996, 274:1133-1138. 36. Kim E, Sheng M: PDZ domain proteins of synapses. Nat Rev Neurosci 2004, 5:771-781. 37. El-Husseini AE, Schnell E, Chetkovich DM, Nicoll RA, Bredt DS: PSD-95 involvement in maturation of excitatory synapses. Science 2000, 290:1364-1368. 38. Ehrlich I, Klein M, Rumpel S, Malinow R: PSD-95 is required for activity-driven synapse stabilization. Proc Natl Acad Sci U S A 2007, 104:4176-4181. 39. Tyagarajan SK, Fritschy J-M: Gephyrin: a master regulator of neuronal function? Nat Rev Neurosci 2014, 15:141-156. 40. Matt L, Kim K, Hergarden AE, Patriarchi T, Malik ZA, Park DK, Chowdhury D, Buonarati OR, Henderson PB, Go¨kc¸ek Sarac¸ C¸ et al.: a-Actinin anchors PSD-95 at postsynaptic sites. Neuron 2018 http://dx.doi.org/10.1016/j.neuron.2018.01.036. 41. Boyken J, Grønborg M, Riedel D, Urlaub H, Jahn R, Chua JJE: Molecular profiling of synaptic vesicle docking sites reveals novel proteins but few differences between glutamatergic and GABAergic synapses. Neuron 2013, 78:285-297. 42. Toth AB, Terauchi A, Zhang LY, Johnson-Venkatesh EM, Larsen DJ, Sutton MA, Umemori H: Synapse maturation by activity-dependent ectodomain shedding of SIRPa. Nat Neurosci 2013, 16:1417-1425. 43. Kaeser PS, Deng L, Cha´vez AE, Liu X, Castillo PE, Su¨dhof TC: ELKS2alpha/CAST deletion selectively increases neurotransmitter release at inhibitory synapses. Neuron 2009, 64:227-239. 44. Hanse E, Seth H, Riebe I: AMPA-silent synapses in brain development and pathology. Nat Rev Neurosci 2013, 14:839-850. 45. Ko J, Kim S, Chung HS, Kim K, Han K, Kim H, Jun H, Kaang B-K, Kim E: SALM synaptic cell adhesion-like molecules regulate the differentiation of excitatory synapses. Neuron 2006, 50:233-245. 46. Kalashnikova E, Lorca RA, Kaur I, Barisone GA, Li B, Ishimaru T, Trimmer JS, Mohapatra DP, Dı´az E: SynDIG1: an activityregulated, AMPA-receptor-interacting transmembrane protein that regulates excitatory synapse development. Neuron 2010, 65:80-93. 47. Pelkey KA, Barksdale E, Craig MT, Yuan X, Sukumaran M, Vargish GA, Mitchell RM, Wyeth MS, Petralia RS, Chittajallu R et al.: Pentraxins coordinate excitatory synapse maturation and circuit integration of parvalbumin interneurons. Neuron 2015, 85:1257-1272. 48. Favuzzi E, Marques-Smith A, Deogracias R, Winterflood CM, Sa´nchez-Aguilera A, Mantoan L, Maeso P, Fernandes C, Ewers H, Rico B: Activity-dependent gating of parvalbumin interneuron function by the perineuronal net protein Brevican. Neuron 2017, 95 639–655.e10. This paper reveals a cell-specific molecular program through which a perineuronal net protein regulates the excitatory but not inhibitory inputs selectively onto PV+ interneurons both during development and upon experience-dependent plasticity. 49. Tao Y, Chen Y-J, Shen C, Luo Z, Bates CR, Lee D, Marchetto S, Gao T-M, Borg J-P, Xiong W-C et al.: Erbin interacts with TARP g-2 for surface expression of AMPA receptors in cortical interneurons. Nat Neurosci 2013, 16:290-299. 50. Jang S, Oh D, Lee Y, Hosy E, Shin H, van Riesen C, Whitcomb D, Warburton JM, Jo J, Kim D et al.: Synaptic adhesion molecule Current Opinion in Neurobiology 2018, 53:8–15
IgSF11 regulates synaptic transmission and plasticity. Nat Neurosci 2016, 19:84-93. 51. Ge Y, Kang Y, Cassidy RM, Moon K-M, Lewis R, Wong ROL, Foster LJ, Craig AM: Clptm1 limits forward trafficking of GABAA receptors to scale inhibitory synaptic strength. Neuron 2018, 97 596–610.e8. 52. Yamasaki T, Hoyos-Ramirez E, Martenson JS, Morimoto Tomita M, Tomita S: GARLH family proteins stabilize GABAA receptors at synapses. Neuron 2017, 93 1138–1152.e6. This paper pushes forward our understanding of the molecular composition of inhibitory postsynapses. The authors show that transmembrane GARLH family proteins form a tripartite complex with GABAARs and NL2 and that disrupting GARLH expression reduces the synaptic localization of the g g2-containing GABAARs and GABAAR-mediated synaptic transmission. 53. Sylwestrak EL, Ghosh A: Elfn1 regulates target-specific release probability at CA1-interneuron synapses. Science 2012, 338:536-540. This paper shows that functional synapse diversity can be triggered at the presynaptic release site depending on the expression of the LRR protein Elfn1 from the postsynaptic target. Using a combination of knockdown and overexpression techniques, the authors show that synapses made by pyramidal cell axons onto a subgroup of SST+ cells are strongly facilitating as a result of Elfn1 function, whereas those made onto PV+ cells, that do not express Elfn1, are depressing. 54. Spiegel I, Mardinly AR, Gabel HW, Bazinet JE, Couch CH, Tzeng CP, Harmin DA, Greenberg ME: Npas4 regulates excitatory-inhibitory balance within neural circuits through cell-type-specific gene programs. Cell 2014, 157:1216-1229. This paper shows that neuronal activity induces expression of Npas4 in both excitatory and inhibitory neurons. The late-response genes induced in the two cell types are, however, very different: they promote inhibition onto excitatory neurons while inducing excitation onto SST+ inhibitory neurons. This combined regulation facilitates a precise circuit response to sensory experience. 55. Lin Y, Bloodgood BL, Hauser JL, Lapan AD, Koon AC, Kim T-K, Hu LS, Malik AN, Greenberg ME: Activity-dependent regulation of inhibitory synapse development by Npas4. Nature 2008, 455:1198-1204. 56. Vuong CK, Black DL, Zheng S: The neurogenetics of alternative splicing. Nat Rev Neurosci 2016, 17:265-281. 57. Traunmu¨ller L, Gomez AM, Nguyen T-M, Scheiffele P: Control of neuronal synapse specification by a highly dedicated alternative splicing program. Science 2016, 352:982-986. This paper demonstrates that a synapse type-specific splicing program orchestrates neuronal synapse specification. Deletion of the RNA-binding protein SLM2 selectively impacts glutamatergic transmission and plasticity by affecting only few transcripts which were critically involved in excitatory synapse development. The structural, functional and behavioral deficits of SLM2 KO mice could be rescued by restoration of a single SLM2-dependent target exon in the synaptic recognition molecule neurexin-1. 58. Berryer MH, Chattopadhyaya B, Xing P, Riebe I, Bosoi C, Sanon N, Antoine-Bertrand J, Le´vesque M, Avoli M, Hamdan FF et al.: Decrease of SYNGAP1 in GABAergic cells impairs inhibitory synapse connectivity, synaptic inhibition and cognitive function. Nat Commun 2016, 7:13340. 59. Chattopadhyaya B, Baho E, Huang ZJ, Schachner M, Di Cristo G: Neural cell adhesion molecule-mediated Fyn activation promotes GABAergic synapse maturation in postnatal mouse cortex. J Neurosci 2013, 33:5957-5968. 60. Tai Y, Janas JA, Wang C-L, Van Aelst L: Regulation of chandelier cell cartridge and bouton development via DOCK7-mediated ErbB4 activation. Cell Rep 2014, 6:254-263. 61. Fossati M, Pizzarelli R, Schmidt ER, Kupferman JV, Stroebel D, Polleux F, Charrier C: SRGAP2 and its human-specific paralog co-regulate the development of excitatory and inhibitory synapses. Neuron 2016, 91:356-369. 62. Del Pino I, Brotons-Mas JR, Marques-Smith A, Marighetto A, Frick A, Marı´n O, Rico B: Abnormal wiring of CCK+ basket cells disrupts spatial information coding. Nat Neurosci 2017, 20:784-792. www.sciencedirect.com
Cortical excitatory and inhibitory synapse formation Favuzzi and Rico 15
63. Del Pino I, Garcı´a-Frigola C, Dehorter N, Brotons-Mas JR, AlvarezSalvado E, Martı´nez de Lagra´n M, Ciceri G, Gabaldo´n MV, Moratal D, Dierssen M et al.: Erbb4 deletion from fast-spiking interneurons causes schizophrenia-like phenotypes. Neuron 2013, 79:1152-1168. 64. Ting AK, Chen Y, Wen L, Yin D-M, Shen C, Tao Y, Liu X, Xiong W-C, Mei L: Neuregulin 1 promotes excitatory synapse development and function in GABAergic interneurons. J Neurosci 2011, 31:15-25.
68. Mardinly AR, Spiegel I, Patrizi A, Centofante E, Bazinet JE, Tzeng CP, Mandel-Brehm C, Harmin DA, Adesnik H, Fagiolini M et al.: Sensory experience regulates cortical inhibition by inducing IGF1 in VIP neurons. Nature 2016, 531:371-375. 69. Gulya´s AI, Megı´as M, Emri Z, Freund TF: Total number and ratio of excitatory and inhibitory synapses converging onto single interneurons of different types in the CA1 area of the rat hippocampus. J Neurosci 1999, 19:10082-10097. 70. Spruston N: Pyramidal neurons: dendritic structure and synaptic integration. Nat Rev Neurosci 2008, 9:206-221.
65. Weng F-J, Garcia RI, Lutzu S, Alvin˜a K, Zhang Y, Dushko M, Ku T, Zemoura K, Rich D, Garcia-Dominguez D et al.: Npas4 is a critical regulator of learning-induced plasticity at mossy fiber-CA3 synapses during contextual memory formation. Neuron 2018 http://dx.doi.org/10.1016/j.neuron.2018.01.026.
71. Fritschy J-M, Panzanelli P, Tyagarajan SK: Molecular and functional heterogeneity of GABAergic synapses. Cell Mol Life Sci 2012, 69:2485-2499.
66. Lisman J, Cooper K, Sehgal M, Silva AJ: Memory formation depends on both synapse-specific modifications of synaptic strength and cell-specific increases in excitability. Nat Neurosci 2018 http://dx.doi.org/10.1038/s41593-018-0076-6.
72. Paul A, Crow M, Raudales R, He M, Gillis J, Huang ZJ: Transcriptional architecture of synaptic communication delineates gabaergic neuron identity. Cell 2017, 171 522–539. e20.
67. Bloodgood BL, Sharma N, Browne HA, Trepman AZ, Greenberg ME: The activity-dependent transcription factor NPAS4 regulates domain-specific inhibition. Nature 2013, 503:121-125.
73. Tremblay R, Lee S, Rudy B: Gabaergic interneurons in the neocortex: from cellular properties to circuits. Neuron 2016, 91:260-292.
www.sciencedirect.com
Current Opinion in Neurobiology 2018, 53:8–15