Diminished hippocalcin expression in Huntington's disease brain does not account for increased striatal neuron vulnerability as assessed in primary neurons.

Hippocalcin is a neuronal calcium sensor protein previously implicated in regulating neuronal viability and plasticity. Hippocalcin is the most highly expressed neuronal calcium sensor in the medium spiny striatal output neurons that degenerate selectively in Huntington's disease (HD). We have previously shown that decreased hippocalcin expression occurs in parallel with the onset of disease phenotype in mouse models of HD. Here we show by in situ hybridization histochemistry that hippocalcin RNA is also diminished by 63% in human HD brain. These findings lead us to hypothesize that diminished hippocalcin expression might contribute to striatal neurodegeneration in HD. We tested this hypothesis by assessing whether restoration of hippocalcin expression would decrease striatal neurodegeneration in cellular models of HD comprising primary striatal neurons exposed to mutant huntingtin, the mitochondrial toxin 3-nitropropionic acid or an excitotoxic concentration of glutamate. Counter to our hypothesis, hippocalcin expression did not improve the survival of striatal neurons under these conditions. Likewise, expression of hippocalcin together with interactor proteins including the neuronal apoptosis inhibitory protein did not increase the survival of striatal cells in cellular models of HD. These results indicate that diminished hippocalcin expression does not contribute to HD-related neurodegeneration.

Differential D1 and D2 receptor-mediated effects on immediate early gene induction in a transgenic mouse model of Huntington's disease.

The diminished expression of D1 and D2 dopamine receptors is a well-documented hallmark of Huntington's disease (HD), but relatively little is known about how these changes in receptor populations affect the dopaminergic responses of striatal neurons. Using transgenic mice expressing an N-terminal portion of mutant huntingtin (R6/2 mice), we have examined immediate early gene (IEG) expression as an index of dopaminergic signal transduction. c-fos, jun B, zif268, and N10 mRNA levels and expression patterns were analyzed using quantitative in situ hybridization histochemistry following intraperitoneal administration of selective D1 and D2 family pharmacological agents (SKF-82958 and eticlopride). Basal IEG levels were generally lower in the dorsal subregion of R6/2 striata relative to wild-type control striata at 10-11 weeks of age, a finding in accord with previously reported decreases in D1 and adenosine A2A receptors. D2-antagonist-stimulated IEG expression was significantly reduced in the striata of transgenic animals. In contrast, D1-agonist-induced striatal R6/2 IEG mRNA levels were either equivalent or significantly enhanced relative to control levels, an unexpected result given the reduced level of D1 receptors in R6/2 animals. Understanding the functional bases for these effects may further elucidate the complex pathophysiology of Huntington's disease.