Date of Award

12-2010

Document Type

Thesis

Degree Name

Master of Science (MS)

Program

Biomedical Sciences

Track

Anatomy and Neuroscience

Research Advisor

Anton Reiner, Ph.D.

Committee

Angela Cantrell, Ph.D. Ioannis Dragatsis, Ph.D.

Abstract

A prominent theory for the pathology of Huntington's Disease (HD) is the excitotoxic injury to the striatum. Continual exposure of ionotropic NMDA receptors to glutamate from the cortex can be excitotoxic in HD and leave striatal neurons vulnerable to damage. Activation of presynaptic mGluR2/3 by an agonist dampens glutamate release from corticostriatal terminals. Treatments that target excitoxicity and oxidative stress thus may improve some of the symptoms in HD patients and it is therefore logical to pursue therapies aimed in this direction. LY379268 is an inviting mGluR2/3 agonist that has been shown to be neuroprotective in hypoxic and ischemic injuries to cultured neurons. Daily subcutaneous injection of 20mg/kg LY379268 had a number of beneficial effects in R6/2 mice, including an 11% improvement in lifespan and various locomotor parameters. The drug showed improvement in open field measurements of overall activity, speed, acceleration, and endurance. Histological and tissue analysis revealed a reduced lateral ventricle enlargement when compared to vehicle-treated R6/2 mice. There was a 20% loss of cortical and striatal neurons in R6/2 mice, which was rescued with the administration of LY379268. There was no effect of the drug on neuronal intranuclear inclusions (NIIs) or ENK+ striatal neurons, but SP+ striatal projection neurons were normalized in their neurochemistry. The R6/2 data indicate that LY379268 is particularly useful in improving the health and functioning of the direct striatal pathway (i.e. SP+ neurons), which demonstrably improved the voluntary motor behavior in the R6/2 mice.

DOI

10.21007/etd.cghs.2010.0170

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