The ataxic groggy rat has a missense mutation in the P/Q-type voltage-gated Ca2+ channel alpha1A subunit gene and exhibits absence seizures.
The groggy rat (strain name; GRY) exhibits ataxia, an unstable gait, and paroxysmal severe extension of the entire body. Adults show a reduction in size of the cerebellum and presynaptic and axon terminal abnormalities of Purkinje cells. These neurological abnormalities are inherited in an autosomal recessive manner, and the causative mutation has been named groggy (gry). In this study, we mapped gry on rat chromosome 19 and found a nonconservative missense (M251K) mutation in the alpha(1A) subunit of the P/Q-type voltage-gated Ca(2+) channel gene (Cacna1a) within the gry-critical region. This mutation was located at a highly conserved site close to the ion-selective pore and led to the shortening of the inactivation phase of the Ca(2+) channel current without a change of peak current density or current-voltage relationship in whole cell patch recordings of the recombinant Ca(2+) channel expressed in HEK cells. It has been well established that mice with a mutation at Cacna1a such as tottering and leaner show absence seizures. The Cacna1a-mutant GRY rat also exhibited absence-like seizures from 6 to 8 weeks of age, which were characterized by bilateral and synchronous 7-8 Hz spike-and-wave discharges concomitant with sudden immobility and staring, on cortical and hippocampal EEGs. The pharmacological profile of the seizures was similar to that of human absence epilepsy: the seizures were inhibited by ethosuximide and valproic acid but not phenytoin. Thus, the GRY rat with P/Q-type Ca(2+) channel disorders is a useful model for studying absence epilepsy and Cacna1a-related diseases.
Tokuda
Satoko
S
Institute of Laboratory Animals, Graduate School of Medicine, Kyoto University, Yoshidakonoe-cho, Sakyo-ku, Kyoto, 606-8501 Japan.
Kuramoto
Takashi
T
Tanaka
Kenta
K
Kaneko
Shuji
S
Takeuchi
Ikuo K
IK
Sasa
Masashi
M
Serikawa
Tadao
T
D000818:Animals; D001259:Ataxia / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D001921:Brain / Q000378:metabolism* / Q000503:physiopathology; D015220:Calcium Channels / Q000737:chemistry / Q000235:genetics*; D020865:Calcium Channels, P-Type / Q000737:chemistry / Q000235:genetics*; D002460:Cell Line; D002462:Cell Membrane / Q000737:chemistry / Q000235:genetics; D002540:Cerebral Cortex / Q000378:metabolism / Q000503:physiopathology; D004569:Electroencephalography; D004832:Epilepsy, Absence / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D005260:Female; D006624:Hippocampus / Q000378:metabolism / Q000503:physiopathology; D006801:Humans; D008297:Male; D008564:Membrane Potentials / Q000235:genetics; D020125:Mutation, Missense / Q000235:genetics*; D018408:Patch-Clamp Techniques; D051381:Rats; D011922:Rats, Mutant Strains; D020864:Calcium Channels, N-Type
D015220:Calcium Channels; D020865:Calcium Channels, P-Type; C491367:Cacna1a protein, rat; D020864:Calcium Channels, N-Type