N-type Ca2+ channels are affected by full-length mutant huntingtin expression in a mouse model of Huntington's disease

Abstract

Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by a polyglutamine expansion in the amino-terminal region of the huntingtin (htt) protein. In addition to facilitating neurodegeneration, mutant htt is implicated in HD-related alterations of neurotransmission. Previous data showed that htt can modulate N-type voltage-gated Ca²⁺ channels (Ca_v2.2), which are essential for presynaptic neurotransmitter release. Thus, to elucidate the mechanism underlying mutant htt-mediated alterations in neurotransmission, we investigated how Ca_v2.2 is affected by full-length mutant htt expression in a mouse model of HD (BACHD). Our data indicate that young BACHD mice exhibit increased striatal glutamate release, which is reduced to wild type levels following Ca_v2.2 block. Ca_v2.2 Ca²⁺ current-density and plasma membrane expression are increased in BACHD mice, which could account for increased glutamate release. Moreover, mutant htt affects the interaction between Ca_v2.2 and 2 major channel regulators, namely syntaxin 1A and G_βγ protein. Notably, 12-month old BACHD mice exhibit decreased Cav2.2 cell surface expression and glutamate release, suggesting that Cav2.2 alterations vary according to disease stage.

Keywords: BACHD; G(βγ) subunits; Glutamate; Huntington's disease; N-type Ca(2+) channels; Syntaxin.