GABA is the principal inhibitory neurotransmitter receptor in the human brain, functioning primarily through GABAA receptors. Normal brain function is critically dependent on the strength of GABA synapses, which in turn depends on the abundance postsynaptic GABAA receptors. Abnormalities in GABAA receptor expression are observed in schizophrenia, alcoholism, anxiety disorders and epilepsy, and in some cases are known to play a causal role in disease progression. Drugs that potentiate GABAA receptor function are important tools for physicians to treat anxiety disorders, epilepsy, and insomnia. Therefore, it is important to understand the mechanisms that regulate the abundance and function of GABAA receptors at synapses. This proposal is directed toward understanding how postsynaptic cells regulate GABAA receptor abundance, using the simple model organism Caenorhabditis elegans. C. elegans has a small nervous system, and can be easily studied by physiological, imaging, and genetic techniques. Significantly, considerable evolutionary conservation has been uncovered at the molecular level between GABA neurotransmission in C. elegans and humans, so what we learn in worms will be medically significant. GABA receptors in mammals are regulated homeostatically in response to agonist exposure and alteration of cellular and network activity. We observe comparable regulation of GABA receptors in C. elegans. Using the power of C. elegans genetic and molecular analysis, we will probe the mechanistic basis of GABA receptor homeostatic regulation, with the eventual goal of understanding the relevant signal transduction pathways. This information will be directly applicable to understanding GABA receptor regulation in both normal and abnormal brain function.
Normal brain function is critically dependent on the strength of GABA synapses. The primary determinants of GABA synapse strength are the quantity of GABA released from presynaptic nerve terminals, and the abundance postsynaptic GABAA receptors. Abnormalities in GABAA receptor expression are observed in schizophrenia, alcoholism, anxiety disorders and epilepsy, and in some cases are known to play a causal role in disease progression. This proposal is directed toward understanding the endogenous mechanisms that regulate the strength of GABA synapses, with particular emphasis on mechanisms that regulate GABAA receptor abundance.
