Synapse formation in the C.elegnas nervous system

Project Details

Description

PROJECT SUMMARY. Neurons regulate synaptic activity by regulating the differentiation of the postsynaptic
face of the synapse, including the amount of glutamate receptors that reach the postsynaptic surface. The
signaling molecules that regulate glutamate receptor localization need to be completely elucidated to
understand postsynaptic differentiation. C. elegans has been an excellent model system for studying
glutamate receptors in vivo. The glutamate receptor subunit GLR-1 is required for glutamatergic signaling,
and is localized to postsynaptic clusters between C. elegans neurons in a mechanosensory circuit. Using
forward genetic screens, we have identified multiple genes that regulate the trafficking of GLR-1 to and from
the synapse. One of these genes encodes a PDZ domain protein with orthologs in mammals, and mutations
in this gene result in the failure of glutamatergic synapses to recover from habituation. Another of these
genes encodes a ubiquitin ligase, and mutations in this gene result in the failure of GLR-1 receptors to be
removed from the synapse. We propose three aims for understanding the role of these genes in regulating
glutamatergic synapse. First, we will characterize changes in GLR-1 trafficking during habituation and
recovery of the mechanosensory circuit. Second, we will characterize the molecular and cell biological
function of the ubiquitin ligase with regard to its role in downregulating GLR-1 after habituation. Third, we
will characterize the molecular and cell biological function of our PDZ domain protein with regard to its role in
upregulating GLR-1 after recovery from habituation. The molecular and cell biological function of these new
genes will provide clues to the mechanisms by which glutamate receptors are regulated.
RELEVANCE. Many nervous system disorders, including stroke, trauma, ALS, Alzheimers, and Parkinsons,
involve the killing of neurons by the neurotransmitter glutamate. High levels of glutamate kill neurons by
overactivating their glutamate receptors. It is critical to understand how glutamate receptors are regulated in
order to develop novel applications for the diagnosis, treatment, and prevention of neurological disorders,
particularly those that stem from glutamate-mediated neurodegeneration.
StatusFinished
Effective start/end date7/1/076/30/08

Funding

  • National Institute of Neurological Disorders and Stroke: $360,874.00

ASJC

  • Clinical Neurology

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