Why We Need More Synaptogenic Cell-Adhesion Proteins

COMMENTARY COMMENTARY Why we need more synaptogenic cell-adhesion proteins Nils Brose1 is triggered by membrane depolarization + Department of Molecular Neurobiology, Max Planck Institute of Experimental Medicine, and Ca2 influx. Released neurotransmitters 37075 Göttingen, Germany bind to receptor proteins on the surface of the receiving part of the synapse, the postsynaptic density, and thereby elicit a mem- The mammalian brain is arguably the most development, and how the molecular com- brane potential change in the receiving cell. complex organ that evolution has brought position of synapses is regulated, have been Most synapses in the mammalian forebrain forward. In the human brain, for example, in the focus of neuroscientists for decades. 11 use the neurotransmitter glutamate, which about 10 neurons are connected via some In PNAS, Yim et al. (1) report that different binds to receptors that act as ligand-gated 15 fi 10 synapses to form multiple speci cally cell-adhesion proteins of the Slitrk (Slit- and cation channels and cause membrane depo- connected neural networks, the interplay of Trk-like) family interact with different cell- larization and excitation of the receiving cell. – which controls all body functions. Synapses, surface exposed protein tyrosine phospha- Glutamatergic excitatory synaptic transmis- the key signaling units in the brain, represent tases (PTPs), and thereby allow neurons to sion in the forebrain is counterbalanced yet another level of substantial complexity; recognize each other during synapse forma- by the activity of inhibitory synapses. Most they are intricate molecular machines com- tion and establish different synapse types. of these synapses use the neurotransmitter posed of thousands of different proteins. The Synapses operate by chemical signaling. GABA, whose GABA receptors are ligand- fi A questions as to how the speci city of synaptic The sending part of the synapse, the pre- gated chloride channels that hyperpolarize connections in the face of huge neuron and synaptic bouton, is specialized for the regu- and thus inhibit the receiving cell. The ex- synapse numbers is achieved during brain lated exocytosis of neurotransmitters, which citation-inhibition balance in the brain is maintained within narrow boundaries. Cor- respondingly, persistent alterations in neuro-

A VGlut nal and network activity trigger homeostatic Synaptophysin changes in the function and number of ex- Munc18 citatory and inhibitory synapses to guarantee Synaptic vesicle Liprin Liprin Liprin an appropriate excitation-inhibition balance Mint CASK

PDZ PDZ PDZ PTP PTP PTP (2), and pathological changes of this balance cause brain diseases, such as epilepsy

NMDAR AMPAR Slitrk2 NMDAR Slitrk2 (3) or autism (4). NX NL1 Slitrk1,4,5 Star- Synapses are thought to form in a two-step gazin process, where an initial cell-type–speciﬁc ? ? PDZ PDZ PDZ PDZ PDZ PDZ PDZ PDZ PDZ PDZ PDZ PDZ PDZ PDZ PDZ PDZ PDZ ? contact between two neurons is formed that S-SCAM PSD-95 PSD-95 PSD-95 PSD-95 subsequently matures into a fully functional

GKAP – ﬁ SHANK synapse. Both, the cell-type speci c formation of a nascent synaptic contact and its B VGAT Synaptophysin subsequent maturation, which involves the

Munc18 recruitment of the presynaptic and post- Synaptic vesicle Liprin synaptic protein machineries required for Mint CASK proper synaptic signaling, are mediated by PDZ PDZ PDZ PTPδ synaptic adhesion proteins (5). Because the corresponding postsynaptic receptors and NX NL2 GABAAR Dystro- GABAAR Slitrk3 ? glycan scaffolding proteins are strikingly different

β in glutamatergic and GABAergic synapses Cb PDZ PDZ PDZ ? (Fig. 1), the protein-recruitment processes PDZ S-SCAM

PDZ involved in the formation and maturation

Gephyrin ofthetwosynapsetypesmustbefunda- scaffold mentally different. A substantial number of different synaptic cell-adhesion systems have been shown to control the formation Fig. 1. Comparison of the neurexin-neuroligin and Slitrk-PTP adhesion systems at excitatory (A) and inhibitory (B) synapses. See text for details. AMPAR, AMPA receptor; CASK, calcium/calmodulin-dependent serine protein kinase; Cb, Collybistin; GABAAR, GABAA receptor; GKAP, guanylate kinase associated protein; MINT, Munc18 interacting Author contributions: N.B. wrote the paper. protein; NL, Neuroligin; NMDAR, NMDA receptor; NX, Neurexin; PDZ, PSD-95/disk-large/zona-occludens-1 domain; The author declares no conﬂict of interest. PSD-95, postsynaptic density protein of 95 kDa; PTP, protein tyrosine phosphatase; SHANK, SH3 and ankyrin repeat containing protein; S-SCAM, synaptic scaffolding molecule; Slitrk, Slit- and Trk-like; VGAT, vesicular GABA/glycine See companion article on page 4057. transporter; VGlut, vesicular glutamate transporter. 1E-mail: [email protected].

www.pnas.org/cgi/doi/10.1073/pnas.1300505110 PNAS | March 5, 2013 | vol. 110 | no. 10 | 3717–3718 Downloaded by guest on September 28, 2021 of glutamatergic excitatory synapses, and GABAergic synapses (Fig. 1). Specifically, PDZ-domain–containing scaffold proteins most of them operate by binding PDZ- Slitrk3 interacts with PTPδ to trigger the (6), and neuroligin-2 and neuroligin-4 inter- domain–containing scaffold proteins such as genesis of inhibitory GABAergic synapses, act with collybistin and gephyrin to initiate PSD-95, which then—directly or indirectly— whereas Slitrk1, Slitrk2, Slitrk4, and Slitrk5 the differentiation of inhibitory postsynapses recruit glutamate receptors to the maturing act at excitatory glutamatergic synapses by (7). In contrast, none of the Slitrks except synapse (6). In contrast, GABAergic post- interacting with PTPσ. The action of Slitrk3 Slitrk2 has a potential PDZ-domain binding synapses contain very few PDZ-domain pro- motif that would allow interactions with the teins and instead require the scaffold protein The fascination of the most prevalent scaffold proteins of gluta- gephyrin and, in many cases, its recruitment fi matergic synapses, and Slitrk3, which may factor collybistin to accumulate GABAA recent ndings and the be one of the enigmatic cronies of neuroligin- receptors. As regards the corresponding resulting conclusions 2 and neuroligin-4 in inhibitory synapse cell-adhesion proteins involved, only the formation, lacks recognizable binding sites α/β-dystroglycan complex and two members is particularly evident for collybistin or gephyrin. of the neuroligin family, neuroligin-2 and with regard to the role The considerations above lead to the neuroligin-4, have been shown to operate in of Slitrk3 at inhibitory fascinating conclusion that Slitrks might exert the formation and maturation of inhibitory their synaptogenic effects by unique mecha- postsynaptic signaling complexes (7). synapses. nisms, the elucidation of which represents The α/β-dystroglycan complex binds pre- the most pressing open task left by Yim synaptic adhesion proteins of the neurexin at inhibitory synapses is phenomenologically et al.’s report (1). The fascination of the re- family and the intracellular scaffold protein related to that of neuroligin-2 and neuroligin- cent findings and the resulting conclusions S-SCAM, but how this leads to GABAA re- 4(7),whereastheeffectsoftheotherSlitrk are particularly evident with regard to the role ceptor recruitment to synapses is unknown. family members are reminiscent of most of Slitrk3 at inhibitory synapses. The for- Neuroligin-2 and neuroligin-4 also bind pre- synaptogenic proteins at excitatory synapses, mation and maturation of many GABAergic synaptic neurexins, but in contrast to the including neuroligin-1 (6). synapses in the mammalian forebrain appear α/β-dystroglycan complex, their intracellular The molecular mechanisms by which to be independent of neuroligin-2, neuro- C termini interact directly with gephyrin PTPδ,PTPσ, and the different Slitrks trigger ligin-4, or collybistin (7). Therefore, homologs and bind and activate collybistin, which synapse formation and maturation are or analogs of neuroligin-2, neuroligin-4, and leads to the postsynaptic recruitment of the probably different from the ones seen with collybistin must exist that operate by similar two scaffold proteins and subsequent post- well-established presynaptically or postsyn- mechanisms to recruit gephyrin and GABAA synaptic assembly of GABAA receptors (7). aptically localized synaptogenic adhesion receptors to maturing inhibitory synapses. Strikingly, however, only a subset of inhibi- proteins, such as neurexins or neuroligins. Beyond neuroligin-3, which is present at a tory synapses is dependent upon the presence Whereas neurexins seem to trigger presyn- subset of inhibitory synapses but does not of neuroligin-2, neuroligin-4, or collybistin, apse differentiation by binding to calcium/ bind collybistin (7), Slitrk3 is a very inter- whereas gephyrin is obligatory for most in- calmodulin-dependent serine protein kinase esting candidate substitute for neuroligin-2 hibitory synapses (7). Thus, to explain the (9), PTPδ and PTPσ are likely to operate by and neuroligin-4. It will be interesting to omnipresence and diversity of inhibitory syn- directly interacting with Liprins (10). On see if the synaptogenic effects of Slitrk3 in- apses in the brain, there is a dire need for the postsynaptic side, neuroligin-1 and most volve the recruitment of the well-established alternative synaptogenic adhesion proteins other postsynaptic adhesion proteins of ex- scaffold proteins of inhibitory synapses or that can operate instead of neuroligin-2 or citatory synapses operate by interaction with whether it operates by a different mechanism. neuroligin-4 and their presynaptic interaction partners and that can trigger GABAA

receptor recruitment in a partly collybistin- 1 Yim YS, et al. (2013) Slitrks control excitatory and inhibitory 6 Siddiqui TJ, Craig AM (2011) Synaptic organizing complexes. independent manner. synapse formation with LAR receptor protein tyrosine phosphatases. Curr Opin Neurobiol 21(1):132–143. It is this need that the PNAS article by Proc Natl Acad Sci USA 110:4057–4062. 7 Krueger DD, Tuffy LP, Papadopoulos T, Brose N (2012) The role of 2 Turrigiano GG (2012) Homeostatic synaptic plasticity: Local and neurexins and neuroligins in the formation, maturation, and function Yim et al. (1) addresses. Extending a previous global mechanisms for stabilizing neuronal function. Cold Spring of vertebrate synapses. Curr Opin Neurobiol 22(3):412–422. study by others (8), the authors show that Harb Perspect Biol 4(1):a005736. 8 Takahashi H, et al. (2012) Selective control of inhibitory synapse different members of the Slitrk family of 3 Engel J, Jr. (1996) Excitation and inhibition in epilepsy. Can J Neurol development by Slitrk3-PTPδ trans-synaptic interaction. Nat Neurosci Sci 23(3):167–174. 15(3):389–398, S1–S2. postsynaptic cell-adhesion proteins interact 4 Rubenstein JL, Merzenich MM (2003) Model of autism: 9 Südhof TC (2008) Neuroligins and neurexins link synaptic function with different presynaptic receptor PTPs Increased ratio of excitation/inhibition in key neural systems. Genes to cognitive disease. Nature 455(7215):903–911. Brain Behav 2(5):255–267. 10 Woo J, Kwon S-K, Kim E (2009) The NGL family of leucine-rich to trigger the formation and maturation 5 Yamagata M, Sanes JR, Weiner JA (2003) Synaptic adhesion repeat-containing synaptic adhesion molecules. Mol Cell Neurosci of excitatory glutamatergic or inhibitory molecules. Curr Opin Cell Biol 15(5):621–632. 42(1):1–10.

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