Genetic analysis of glutamate receptor function and regulation in locomotory control in C. elegans.

摘要

Neurons are organized in neuronal circuits to process information and control behavior. One of the fundamental problems in neuroscience is to understand the biological mechanisms that regulate neuronal circuits and contribute to behavior. I have undertaken a powerful new approach that combines molecular, genetic, and behavioral analysis to address this problem. By analyzing the role of ionotropic glutamate receptor function and regulation in a relatively simple neuronal circuit, the locomotory control circuit, in the earth nematode Caenorhabditis elegans, I have furthered our understanding of how neuronal circuits control behavior.; The C. elegans locomotory control circuit is a well-defined circuit that is essential for coordinated movement and avoidance of aversive stimuli. To understand how information is processed in this important circuit, I have developed a novel technique to constitutively activate the central command interneurons in this circuit. By expressing a dominant, active form of the C. elegans non-NMDA type ionotropic glutamate receptor GLR-1 in the command interneurons, I have shown that the duration of directional movement is regulated by depolarization of these neurons. Combined with other genetic means, my analysis has also shown that these interneurons can not be strictly assigned as “forward” movement or “backward” movement interneurons but rather function together as a distributed neuronal pattern generator.; It is now widely accepted that ionotropic glutamate receptors are essential signaling molecules in the vertebrate central nervous system. To further understand the molecular mechanisms that regulate glutamate receptor function, I performed a genetic screen in worms that expressed the dominantly active subunit to identify genes required for glutamate receptor function. I cloned and characterized the sol-1 gene and showed that mutations in this gene result in the same behavioral and electrophysiological defects as observed in glr-1 mutants. sol-1 encodes a novel transmembrane protein that is not required for the expression, trafficking, or membrane insertion of GLR-1. Thus, SOL-1 likely functions as an accessory protein and may bring other proteins together to facilitate the non-NMDA type receptor function.; These analyses have shown that C. elegans can be used to identify novel gene products required for receptor function and thus neuronal function and behavior.