Regulation of GABAergic synapse development by postsynaptic membrane proteins

Abstract

In the adult mammalian brain, GABAergic neurotransmission provides the majority of synaptic inhibition that balances glutamatergic excitatory drive and thereby controls neuronal output. It is generally accepted that synaptogenesis is initiated through highly specific protein-protein interactions mediated by membrane proteins expressed in developing presynaptic terminals and postsynaptic membranes. Accumulating studies have uncovered a number of membrane proteins that regulate different aspects of GABAergic synapse development. In this review, we summarize recent advances in understanding of GABAergic synapse development with a focus on postsynaptic membrane molecules, including receptors, synaptogenic cell adhesion molecules and immunoglobulin superfamily proteins.

Molecular Dissection of Neuroligin 2 and Slitrk3 Reveals an Essential Framework for GABAergic Synapse Development

“…Many transmembrane synaptic CAMs, such as NLs, LRRTMs, neurexins, Slitrks, PTPs, and cadherins, typically use characteristic extracellular domains to mediate trans-synaptic interactions to organize and regulate synapse development and function (de Wit and Ghosh, 2016; Lu et al, 2016; Missler et al, 2012). We now report that at hippocampal GABAergic synapses, two major postsynaptic CAMs, NL2 and ST3, interact with each other in cis to control GABAergic synapse development.…”

“…Among these molecules, synaptic cell adhesion molecules (CAMs) are a class of membrane proteins essential for the establishment and maturation of synaptic connections. Recent studies have identified a growing number of synaptic CAMs, including: 1) Neuroligins (NLs) and leucine-rich repeat transmembrane proteins (LRRTMs) that bind to presynaptic neurexins; 2) Slit and NTRK-like family proteins (Slitrks) that bind to presynaptic protein tyrosine phosphatases (PTPs); 3) immunoglobulin superfamily proteins (IgSFs) that mediate trans-synaptic homophilic or heterophilic adhesion interactions; 4) cadherin family proteins; and 5) transmembrane tyrosine kinase receptors (Craig and Kang, 2007; Dalva et al, 2007; de Wit and Ghosh, 2016; Huang and Scheiffele, 2008; Krueger-Burg et al, 2017; Lu et al, 2016; Missler et al, 2012; Sudhof, 2008). While these molecules are involved in various stages of synapse development, how diverse synaptic CAMs work in concert to control synapse formation remains largely unclear.…”

“…Interestingly, GABAergic synapses exhibit remarkable diversity (Cherubini and Conti, 2001; Sassoe-Pognetto et al, 2011) with over twenty different types of interneurons providing domain-specific, functionally distinct GABAergic input onto principal neurons and each other (Klausberger and Somogyi, 2008). Although many molecules and signaling pathways have been identified to regulate hippocampal GABAergic synapse development (Huang and Scheiffele, 2008; Ko et al, 2015; Krueger-Burg et al, 2017; Kuzirian and Paradis, 2011; Lu et al, 2016), a general framework for development of diverse GABAergic synapses has not been identified.…”

Development of fast neurotransmitter synapses: General principle and recent progress

“…These observations suggest that development of GABAergic synapses involves mechanisms distinct from that of glutamatergic synapses. Nevertheless, convincing evidence has demonstrated that cell adhesion molecules are critical for both excitatory and inhibitory synapse development, suggesting that trans-synaptic interactions are a common requirement for the formation of different types of synapses [4, 6, 10, 12]. Interestingly, distinct sets of cell adhesion molecules are enriched at excitatory vs inhibitory synapses [4, 6, 10, 12], suggesting different synaptogenic machineries present at these synapses to instruct their formation respectively.…”

“…For inhibitory synapses development, Lu et al, [10] discuss the key role of postsynaptic transmembrane molecules in the development of GABAergic inhibitory synapses, including NMDA receptors, GABA A receptors, synaptogenic cell adhesion molecules and immunoglobulin superfamily proteins. Wierenga [20] highlights the importance of local exchange of synaptic adhesion molecules, actin dynamics and activity-driven fine-tuning in GABAergic presynaptic development.…”