Abstract#1

Friday, January 16, 2009

R6/2 Phenotype Dependence on CAG repeat Length
Steven Gee
MARC U*STAR Fellow

R6/2 phenotype dependence on CAG repeat length Steven Gee, Damian Cummings and Michael Levine California State University of Los Angeles and UCLA Neuroscience Program UCLA Huntington’s disease (HD) is a neurodegenerative disease caused by expansion of the repeated CAG codon in the coding region of the huntingtin gene. In humans, the number of CAG repeats is inversely proportional to the age of onset. The R6/2 transgenic mouse is the most studied murine model of HD. Electrophysiological experiments in striatum of the R6/2 mouse have revealed a number of alterations, including a progressive decrease in excitatory postsynaptic current (EPSC) frequency in medium-sized spiny neurons (MSNs) and an increase in inhibitory postsynaptic current (IPSC) frequency. These electrophysiological phenotypes suggest complex alterations in the corticostriatal pathway and may contribute to cellular dysfunction and neuronal cell death in HD. Given the CAG repeat dependency of HD in humans, we hypothesized that R6/2 mice with longer CAG repeats would be more affected than those with shorter repeats. Four lines of R6/2 mice carrying 110, 150, 210, and 310 CAG repeats, respectively, were studied in order to assess the correlation between CAG repeat lengths and electrophysiological phenotype. Whole cell patch clamp experiments were conducted in MSNs in acute slices in each of the R6/2 lines. Both increases in IPSC and decreases in EPSC frequencies were observed in R6/2 MSNs. Mice carrying 110 or 150 repeats exhibited the most severe phenotype while those with 200 repeats or greater exhibited a milder phenotype. Our data suggest that the R6/2 phenotype is greatly dependent on CAG repeat length but in an unexpected ‘U-shaped’ function.  

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