Understanding the Molecular Diversity of GABAergic Synapses

Abstract

GABAergic synapses exhibit a high degree of subcellular and molecular specialization, which contrasts with their apparent simplicity in ultrastructural appearance. Indeed, when observed in the electron microscope, GABAergic synapses fit in the symmetric, or Gray’s type II category, being characterized by a relatively simple postsynaptic specialization. The inhibitory postsynaptic density cannot be readily isolated, and progress in understanding its molecular composition has lagged behind that of excitatory synapses. However, recent studies have brought significant progress in the identification of new synaptic proteins, revealing an unexpected complexity in the molecular machinery that regulates GABAergic synaptogenesis. In this article, we provide an overview of the molecular diversity of GABAergic synapses, and we consider how synapse specificity may be encoded by selective trans-synaptic interactions between pre- and postsynaptic adhesion molecules and secreted factors that reside in the synaptic cleft. We also discuss the importance of developing cataloguing tools that could be used to decipher the molecular diversity of synapses and to predict alterations of inhibitory transmission in the course of neurological diseases.

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

“…GABAergic synapses exhibit an extraordinary diversity in terms of molecular, anatomic and physiological properties (Cherubini and Conti, 2001; Klausberger and Somogyi, 2008; Kubota et al, 2016; Sassoe-Pognetto et al, 2011). In hippocampus, principal neurons are innervated by over twenty distinct types of interneurons (Klausberger and Somogyi, 2008).…”

“…As GABAergic inhibition is important in almost every aspect of brain physiology and the dysregulation of GABAergic synapse development has been implicated in many neurological and neuropsychiatric disorders (Ko et al, 2015; Ramamoorthi and Lin, 2011), it is critical to understand the molecular determinants of GABAergic synapse formation. 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.…”

Genome-wide investigation of schizophrenia associated plasma Ndel1 enzyme activity

“…MAGI2 has been implicated in both glutamatergic (Deng et al, 2006) and GABAergic pathways (Sassoe-Pognetto et al, 2011). SNPs of MAGI2 have been associated with performance in the Wisconsin Sorting Card Test (WCST) in patients with SCZ (Koide et al, 2012), whereas in animal models it was shown to modulate long-term memory and associative learning (Emtage et al, 2009;Stetak et al, 2009).…”

Molecular and functional heterogeneity of GABAergic synapses

“…Rather, they are organized around a core scaffolding protein, gephyrin, which forms multimeric complexes by auto-aggregation and by interacting with other postsynaptic proteins, including GABA A receptors (GABA A R), glycine receptors (GlyR), neuroligins (NL), and collybistin (CB) [13]. Models to explain the formation and maintenance of either glycinergic or GABAergic synapses are still fragmentary [14][15][16], notably because the biochemical composition of their PSD is poorly characterized and because gephyrin structure is only partially resolved. The paucity of PDZ domains in proteins forming GABAergic and glycinergic PSDs implies, however, that protein-protein interactions are based largely on other motifs.…”