Lack of CaV3.1 channels causes severe motor coordination defects and an age-dependent cerebellar atrophy in a genetic model of essential tremor

T-type Ca2+ channels have been implicated in tremorogenesis and motor coordination. The α1 subunit of the CaV3.1 T-type Ca2+ channel is highly expressed in motor pathways in the brain, but knockout of the CaV3.1 gene (α1G-/-α1G-/-) per se causes no motor defects in mice. Thus, the role of CaV3.1 channels in motor control remains obscure in vivo. Here, we investigated the effect of the CaV3.1 knockout in the null genetic background of α1 GABAA receptor (α1−/−) by generating the double mutants (α1−/−/α1G-/-α1G-/-). α1−/−/α1G-/-α1G-/- 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−/−/α1G-/-α1G-/- mice. In addition, α1−/−/α1G-/-α1G-/- mice showed an age-dependent loss of cerebellar Purkinje neurons. These results suggest that α1−/−/α1G-/-α1G-/- mice are a novel mouse model for a distinct subtype of ET in human and that CaV3.1 T-type Ca2+ channels play a role in motor coordination under pathological conditions.

► We investigate the effect of lack of CaV3.1 T-type Ca2+ channels in α1 GABAA receptor-null mice, a mouse model of essential tremor, by generating double knockout mice.
► The double knockout mice exhibit severer tremor that leads to motor coordination defects and Purkinje neuron degeneration as compared with the α1-null mice.
► We provide a novel mouse model for a distinct subtype of essential tremor.
► T-type Ca2+ channels contribute to motor function under pathological condition.