GABA_A Receptor Expression in the Forebrain of Ataxic Rolling Nagoya Mice

The human CACNA1A gene encodes the pore-forming α₁ subunit of Ca_V2.1 (P/Q-type) calcium channels and is the locus for several neurological disorders, including episodic ataxia type 2 (EA2), spinocerebellar ataxia type 6 (SCA6) and Familial Hemiplegic Migraine type 1 (FHM1). Several spontaneous mouse Cacna1a mutant strains exist, among them Rolling Nagoya (tg^rol), carrying the R1262G point mutation in the mouse Cacna1a gene. tg^rol mice display a phenotype of severe gait ataxia and motor dysfunction of the hind limbs. At the functional level, the R1262G mutation results in a positive shift of the activation voltage of the Ca_V2.1 channel and reduced current density. γ-Aminobutyric acid type A (GABA_A) receptor subunit expression depends critically on neuronal calcium influx, and GABA_A receptor dysfunction has previously been described for the cerebellum of tg^rol and other ataxic Cacna1a mutant mice. Given the expression pattern of Ca_V2.1, it was hypothesized that calcium dysregulation in tg^rol might affect GABA_A receptor expression in the forebrain. Herein, functional GABA_A receptors in the forebrain of tg^rol mice were quantified and pharmacologically dissociated using [³H] radioligand binding. No gross changes to functional GABA_A receptors were identified. Future cell type-specific analyses are required to identify possible cortical contributions to the psychomotor phenotype of tg^rol mice.