A network of autism linked genes stabilizes two pools of synaptic GABAA receptors

  • Tong X
  • Hu Z
  • Liu Y
  • et al.
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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 GABAA receptors are stabilized by distinct synaptic scaffolds at C. elegans neuromuscular junctions. Immobilized GABAA receptors are stabilized by binding to FRM-3/EPB4.1 and LIN-2A/CASK. Diffusing GABAA 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.Behaviors ranging from movement to memory are dependent on the activity of extensive networks of cells called neurons. Within these networks, neurons communicate across junctions called synapses. The arrival of an electrical signal called an action potential at the ‘presynaptic’ neuron on one side of the synapse triggers the neuron to release chemical neurotransmitter molecules into the synapse. These molecules then bind to receptors on the ‘postsynaptic’ cell on the other side of the synapse.At excitatory synapses, the binding of neurotransmitter to postsynaptic receptors increases the likelihood that the postsynaptic cell will fire its own action potential. By contrast, at inhibitory synapses the binding of neurotransmitters reduces the chances of the postsynaptic cell firing. Most inhibitory synapses use a type of neurotransmitter called GABA, which exerts its effects mainly by binding to a class of receptors called GABA-activated chloride channels (also known as GABAA receptors).GABAA receptors at inhibitory synapses can themselves be divided into two groups: ‘mobile’ receptors, which can move within the cell membrane that surrounds the postsynaptic cell; and ‘immobilized’ receptors that form clusters and cannot move. Recent work in mammalian cells identified a protein complex that anchors GABAA receptors to the cell's internal skeleton to immobilize the receptors. However, there is evidence to suggest that these are not the only proteins that control the location of the receptors.By studying the inhibitory synapses formed between neurons and body muscles in the roundworm species Caenorhabditis elegans, Tong, Hu et al. now show that different groups of proteins maintain the positioning of immobilized and mobile receptors. Specifically, proteins called LIN-2A (a component of the cell's internal skeleton) and FRM-3 (which joins receptors to the cell's skeleton) immobilize GABAA receptors, whilst the proteins Neuroligin and Neurexin ensure that mobile GABAA receptors remain within the synapse.Disturbances to the activity of inhibitory synapses are often seen in autism spectrum disorders, and so too are mutations in the genes that encode the mammalian equivalents of Neuroligin, Neurexin and LIN-2A. The work of Tong, Hu et al. thus suggests a mechanism by which these mutations might contribute to information processing impairments in people with autism. Further research could now investigate if (and how) other genes linked to autism spectrum disorders alter inhibitory synapses.




Tong, X.-J., Hu, Z., Liu, Y., Anderson, D., & Kaplan, J. M. (2015). A network of autism linked genes stabilizes two pools of synaptic GABAA receptors. ELife, 4. https://doi.org/10.7554/elife.09648

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