A network of autism linked genes stabilizes two pools of synaptic GABA(A) receptors.

Xia-Jing Tong,Zhitao Hu,Joshua M Kaplan,Dorian Anderson,Yu Liu

doi:10.7554/elife.09648

Abstract

Changing receptor abundance at synapses is an important mechanism for regulating synaptic strength. Synapses contain two pools of receptors, immobilized and diffusing receptors, both of which are confined to post-synaptic elements. Here we show that immobile and diffusing GABA(A) receptors are stabilized by distinct synaptic scaffolds at C. elegans neuromuscular junctions. Immobilized GABA(A) receptors are stabilized by binding to FRM-3/EPB4.1 and LIN-2A/CASK. Diffusing GABA(A) receptors are stabilized by the synaptic adhesion molecules Neurexin and Neuroligin. Inhibitory post-synaptic currents are eliminated in double mutants lacking both scaffolds. Neurexin, Neuroligin, and CASK mutations are all linked to Autism Spectrum Disorders (ASD). Our results suggest that these mutations may directly alter inhibitory transmission, which could contribute to the developmental and cognitive deficits observed in ASD.

Highlights

Fast synaptic inhibition is primarily mediated by the neurotransmitter GABA and GABA-activated chloride channels (GABAA receptors)
We show that immobilized and diffusing GABAA receptors are stabilized by two distinct post-synaptic scaffolds both of which contain subunits encoded by genes linked to Autism Spectrum Disorders (ASD)
Mutants lacking UNC-49 receptors have defects in GABA-activated muscle currents, as assessed by recording miniature inhibitory post-synaptic currents and muscle currents evoked by an exogenous GABA agonist (Figure 1A–E)

Summary

Introduction

Fast synaptic inhibition is primarily mediated by the neurotransmitter GABA and GABA-activated chloride channels (GABAA receptors). Variation in the amplitude of miniature inhibitory post-synaptic currents (mIPSCs) is caused by corresponding differences in the abundance of GABAA receptors at synapses (Nusser et al, 1997). GABAA diffusion is significantly reduced at synapses, resulting in accumulation of receptors at the synapse (Jacob et al, 2005; Thomas et al, 2005; Bannai et al, 2009; Petrini et al, 2014). The post-synaptic scaffold that immobilizes GABAA receptors is proposed to consist of a ternary complex of Gephyrin, Neuroligin-2 (NL2), and collybistin (Jacob et al, 2005; Poulopoulos et al, 2009). It is likely that additional proteins are involved in this process

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