Identification and characterization of genes that regulate GABA synapses

Cognition and behavior depend upon a precise balance of synaptic activity within circuits of interconnected neurons. Inhibitory GABAergic synapses play a critical role in many aspects of circuit development and function and are necessary to maintain this circuit balance. For example, conditions that perturb GABA transmission have been implicated in epilepsy, autism, and schizophrenia. The biological basis of this balance has historically been difficult to study due to the complex circuitry of the mammalian brain. Body muscles at neuromuscular junctions of the nematode C. elegans receive both excitatory and inhibitory neuronal inputs, making this an ideal model system for identifying genes that are needed to maintain circuit balance. We used RNA interference to screen for genes whose inactivation increased the activity of C. elegans body muscles, identifying 90 genes. Using electrophysiological recordings and imaging of excitatory and inhibitory synapses, we determined that several of these genes alter muscle activity by selectively regulating inhibitory transmission. In particular, we identify two humoral pathways and several protein kinases that modulate GABA transmission but have little effect on excitatory transmission at cholinergic neuromuscular junctions. Our data suggest these conserved genes are components of signaling pathways that regulate GABA transmission, and consequently may play a role in epilepsy and other cognitive or psychiatric disorders.