GABA and neuroligin signaling: linking synaptic activity and adhesion in inhibitory synapse development

Abstract

GABA-mediated synaptic inhibition is crucial in neural circuit operations. In mammalian brains, the development of inhibitory synapses and innervation patterns is often a prolonged postnatal process, regulated by neural activity. Emerging evidence indicates that gamma-aminobutyric acid (GABA) acts beyond inhibitory transmission and regulates inhibitory synapse development. Indeed, GABA(A) receptors not only function as chloride channels that regulate membrane voltage and conductance but also play structural roles in synapse maturation and stabilization. The link from GABA(A) receptors to postsynaptic and presynaptic adhesion is probably mediated, partly by neuroligin-reurexin interactions, which are potent in promoting GABAergic synapse formation. Therefore, similar to glutamate signaling at excitatory synapse, GABA signaling may coordinate maturation of presynaptic and postsynaptic sites at inhibitory synapses. Defining the many steps from GABA signaling to receptor trafficking/stability and neuroligin function will provide further mechanistic insights into activity-dependent development and possibly plasticity of inhibitory synapses.

Figure 1

GAD67 and GABA act beyond inhibitory transmission and regulate inhibitory synapse development. (a) GABA signaling may regulate the morphogenesis (e.g. growth and stability) of inhibitory synapses. (b) Since synapse formation is an integral part of axon growth and branching, activity-dependent GABA signaling may further influence the development of GABAergic axon arbor and innervation pattern.

Figure 2

A hypothetical model depicting how GABA-GABA_AR signaling and neuroligin-neurexin adhesion may interact and cooperate to regulate the development of inhibitory synapses. Pentameric GABA_ARs are assembled in the endoplasmic reticulum and are subject to activity-dependent proteasomal degradation. Most GABA_ARs are first delivered to extrasynaptic locations, they then either diffuse to and become trapped at postsynaptic sites or undergo endocytosis. NL2 and synaptic GABA_AR stabilize each other, either through intracellular reciprocal interactions aided by scaffolding proteins such as gephyrin or through extracellular cis interaction. In addition, GABA activation of GABAARs might further stabilize synaptic GABA_ARs through structural changes or signaling mechanisms. Such activity- and GABA-mediated stabilization of GABA_AR might further increase the levels of NL2 at cell-cell contacts and, in turn, stabilize presynaptic terminals through trans-synaptic interactions with neurexins.