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J Neurophysiol (December 28, 2005). doi:10.1152/jn.01118.2005
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01118.2005v1
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Submitted on October 24, 2005
Accepted on December 23, 2005

Altered cortical glutamate receptor function in the R6/2 model of Huntington's disease

Veronique M. Andre1*, Carlos Cepeda1, Angela L. Venegas1, Yeranui Gomez1, and Michael S. Levine1

1 Mental Retardation Research Center, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA, USA

* To whom correspondence should be addressed. E-mail: vandre{at}mednet.ucla.edu.

Alterations in pyramidal neurons from the sensorimotor cortex may be responsible for some of the cognitive and motor symptoms of Huntington's disease (HD). The present experiments used R6/2 transgenic mice which express exon 1 of the human HD gene with an expanded number of CAG repeats. We characterized alpha-amino-3-hydroxy-5-methyl-4-propionate (AMPA) currents and their modulation by cyclothiazide (CTZ) as well as N-methyl-D-aspartate (NMDA) currents and their Mg2+ sensitivity in acutely dissociated cortical pyramidal neurons in R6/2 transgenic mice and wild type (WT) mice at 21 days (before overt symptoms), 40 days (when symptoms begin) and 80 days (fully symptomatic). AMPA currents, alone or in the presence of CTZ, were smaller in 21 and 40 day old R6/2 groups compared to WT mice. In R6/2 mice, more neurons displayed desensitizing AMPA currents in the presence of CTZ, indicating increased expression of flop splice variants, while the majority of WT cells expressed the flip variants of AMPA receptor subunits. NMDA peak currents also were smaller in R6/2 pyramidal neurons at 21 days. At 40 days, NMDA currents were similar in WT and R6/2 mice but Mg2+ sensitivity was greater in R6/2 mice, resulting in smaller NMDA currents in the presence of Mg2+. Differences in AMPA and NMDA currents between WT and R6/2 cells were no longer detected at 80 days. Our findings indicate that currents induced by glutamate receptor agonists are decreased in isolated cortical pyramidal neurons from R6/2 mice and that this decrease occurs early. Altered glutamate receptor function could contribute to changes in cortical output and may underlie some of the cognitive and motor impairments in this animal model of HD.




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