UC San Diego

Behaviors of animals require the coordinated activity of excitatory and inhibitory transmission within neural circuits. Imbalanced neuronal circuit activity is an underlying cause of many neuronal disorders such as epilepsy. Thus, understanding the mechanisms of how the balanced neural activity is maintained and what occurs when this E/I balance is disrupted will provide insights for developing effective treatment of disease conditions. In my thesis, I addressed these questions using the relatively simple locomotory motor neuron circuit of C. elegans. It was previously reported that an activating mutation acr-2(gf) in an acetylcholine (ACh) receptor subunit ACR-2 expressed in neruons causes muscle hyper-contraction, which leads to the animal’s spontaneous shrinking behavior termed convulsion. The mutant exhibits overexcitation of cholinergic motor neuron activity accompanied by suppression of GABAergic motor neuron activity, resulting in E/I imbalance in the motor neuron circuit. Through studies of a genetic suppressor of acr-2(gf), I characterized a ligand-gated ion channel which localizes to the presynaptic terminals and functions to suppress cholinergic motor neuron activity. Next, I identified the neuropeptide pathway that is suppresses the E/I imbalance, and Using the acr-2(gf) convulsion as the model of E/I imbalance, we found that animals express specific neuropeptides upon overexcitation of neurons to suppress the imbalance. Finally, I identified a mutation in a putative co-chaprone protein that exacerbates the convulsion phenotype of acr-2(gf). My thesis work characterizes multiple pathways that regulate the E/I balance within a neural circuit.