The ataxic groggy rat has a missense mutation in the P/Q-type voltage-gated Ca2+ channel α1A subunit gene and exhibits absence seizures

Abstract

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.

Immunohistochemical Features of Dystrophic Axons in Papillon Dogs with Neuroaxonal Dystrophy

“…34 Among the subtypes of human SCDs, SCA6 is caused by an elongated CAG repeat of the CACNA1A gene encoding the P/Q-type voltagedependent calcium channel. 13 Several murine models with mutations at the a1 subunit of the gene such as groggy rat 49,52 are thought to have some clinical and pathologic similarity with canine NAD. To discuss the relationship between the calcium channel and canine NAD, further molecular investigations, including gene analysis, are necessary.…”

The Role of Calcium Channels in Epilepsy

“…A spontaneous recessive mutation in CACNA1A was identified in the groggy (GRY), which shows absence seizures similar to the tottering mouse series, ataxia, and paroxysmal dyskinesia. The mutation, M251K, located close to the ion selective pore is associated with a small cerebellum and abnormalities of Purkinje cells (Tokuda et al 2007). …”

Serotonergic Modulation of Absence-Like Seizures in Groggy Rats: a Novel Rat Model of Absence Epilepsy

“…Surgical procedures for the electrode implantation and EEG recordings were performed as described previously (20,22). Since it was confirmed in the preliminary experiments that both male and female rats exhibited SWD with a similar frequency, GRY rats of either sex (250 -350 g) were employed.…”

“…More recently, Tokuda et al (20) showed that GRY rats carry a missense (M251K) mutation in the gene encoding the α 1A subunit of the P/Q type voltage-dependent Ca 2+ channel (Cacna1a) and, like the Cacna1a mutant tottering mice (21), exhibit absence-like seizures associated with 7 -8 Hz spike and wave discharges (SWD) and concomitant immobile postures. In addition, absence-like seizures in GRY rats were significantly alleviated by two antiepileptic drugs effective for human absence seizures, ethosuximide and sodium valproic acid, but not by phenytoin that lacks efficacy for absence seizures (20). These analyses of seizure phenotypes reveal that GRY rats are useful as a novel model of human absence epilepsy.…”

“…The present study using GRY rats, a novel rat model of absence epilepsy (20), demonstrated that both (±)8-OH-DPAT and (±)DOI markedly inhibited the incidence of SWD associated with the absence-like behavior. In addition, stimulation of the serotonergic system by the 5-HT reuptake inhibitors fluoxetine and clomipramine also inhibited the SWD generation.…”