Lack of Ca V3.1 channels causes severe motor coordination defects and an age-dependent cerebellar atrophy in a genetic model of essential tremor

Abstract

T-type Ca 2+ channels have been implicated in tremorogenesis and motor coordination. The α1 subunit of the Ca V3.1 T-type Ca 2+ channel is highly expressed in motor pathways in the brain, but knockout of the Ca V3.1 gene ( α 1 G - / - ) per se causes no motor defects in mice. Thus, the role of Ca V3.1 channels in motor control remains obscure in vivo. Here, we investigated the effect of the Ca V3.1 knockout in the null genetic background of α1 GABA A receptor (α1 −/−) by generating the double mutants (α1 −/−/ α 1 G - / - ). α1 −/−/ α 1 G - / - mice showed severer motor abnormalities than α1 −/− mice as measured by potentiated tremor activities at 20 Hz and impaired motor learning. Propranolol, an anti-ET drug that is known to reduce the pathologic tremor in α1 −/− mice, was not effective for suppressing the potentiated tremor in α1 −/−/ α 1 G - / - mice. In addition, α1 −/−/ α 1 G - / - mice showed an age-dependent loss of cerebellar Purkinje neurons. These results suggest that α1 −/−/ α 1 G - / - mice are a novel mouse model for a distinct subtype of ET in human and that Ca V3.1 T-type Ca 2+ channels play a role in motor coordination under pathological conditions.