Cell-intrinsic mechanisms that regulate the activity of dopamine (DA) neurons and the cells that innervate are not well understood, and might be important targets for the treatment of neurological and psychiatric disorders caused by dysfunction of brain DA systems. C. elegans offers the opportunity to use behavior-based approaches to discover novel regulators of DA signaling. C. elegans contains eight DA neurons that mediate stereotyped behaviors and are accessible to molecular, genetic, and physiological analysis.
First, I conducted experiments that integrate transcriptomic analysis of dopamine neurons and a machine-vision-based behavioral screen to identify genes required for the function of dopamine neurons. Through this approach, I identified the K2P-family K+ channel, TWK-2, and discovered that it functions to regulate how DA neurons are activated by appetitive food stimuli. Specifically, TWK-2 channels functionally oppose TRP-4 channels, which are transient receptor potential (TRP) channels required for activation of dopamine neurons. Loss of TWK-2 channels restores physiological function to trp-4 mutant dopamine neurons and also restores a food-response behavior to trp-4 mutants. These data reveal a critical role for a K2P channel in DA neurons and suggest that these ion channels could be therapeutic targets for the treatment of psychiatric and neurological disorders caused by dysfunction of DA systems.
Second, I developed a functional screen for mammalian homologs of C. elegans DA receptors that are ligand-gated ion channels. In vertebrates, DA is thought to signal exclusively through G protein-coupled receptors (GPCRs). The C. elegans nervous system expresses homologs of these GPCRs and also expresses DA-activated Cl− channels that are related to vertebrate GABA and glycine receptors. I hypothesized that there might be vertebrate homologs of these DA-gated channels and performed a functional screen for such homologs. My preliminary results provide support for the hypothesis that DA-gated ion channels can be formed by some assembly of subunits currently annotated as GABAA- and glycine-receptor subunits. This in turn suggests that DA might directly evoke fast inhibitory signals in mammalian neurons expressing these receptors. Together, my studies reveal novel mechanisms of dopamine signaling that might be conserved between nematodes and vertebrates.
|Commitee:||Chao, Moses V., Tsien, Richard W., Rice, Margaret E., Chalfie, Martin|
|School:||New York University|
|Department:||Basic Medical Science|
|School Location:||United States -- New York|
|Source:||DAI-B 81/2(E), Dissertation Abstracts International|
|Subjects:||Neurosciences, Cellular biology, Molecular biology|
|Keywords:||C. elegans, Dopamine, K2P, Mechanosensation, TRP, Two-pore potassium channel|
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