Age-dependent biphasic changes in ischemic sensitivity in the striatum of Huntington's disease R6/2 transgenic mice.
We used the oxygen/glucose deprivation (OGD) model of ischemia in corticostriatal brain slices to test the hypothesis that metabolic deficiencies in R6/2 transgenic Huntington's disease (HD) mice will impair their recovery from an ischemic challenge. Corticostriatal extracellular field excitatory postsynaptic potentials (fEPSPs) were evoked in transgenic and wild-type (WT) mice in three age groups: 3-4 wk, before the overt behavioral phenotype develops; 5-9 wk, as overt behavioral symptoms begin; and 10-15 wk when symptoms were most severe. OGD for 8 min completely and reversibly inhibited fEPSPs. Although responses of 3-4 wk WTs showed a tolerance to ischemia and recovered rapidly, ischemic sensitivity developed progressively; at 5-9 and 10-15 wk, responses recovered more slowly from OGD. In contrast, although 3-4 wk R6/2 transgenic fEPSPs showed significantly more ischemic sensitivity than their WT counterparts, the R6/2 fEPSPs maintained a relative tolerance to ischemia at 5-9 and 10-15 wk. As a result, a "crossover" point occurred, roughly coinciding with the development of the overt behavioral phenotype (5-9 wk), after which time R6/2 fEPSPs were significantly more resistant to ischemia than WT responses. The increased ischemic sensitivity in 3-4 wk R6/2 responses was not due to excessive glutamate release during OGD as it persisted in the presence of the glutamate receptor antagonist kynurenic acid (1 mM). Although the mechanism for development of ischemic resistance in R6/2 transgenics remains unknown, it correlates with metabolic and biochemical changes described in this model and in HD patients.
Klapstein
Gloria J
GJ
Mental Retardation Research Center, The David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
Levine
Michael S
MS
D000367:Age Factors; D000818:Animals; D015687:Cell Hypoxia / Q000502:physiology; D003342:Corpus Striatum / Q000502:physiology*; D019706:Excitatory Postsynaptic Potentials / Q000502:physiology*; D005260:Female; D006816:Huntington Disease / Q000235:genetics / Q000503:physiopathology*; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic