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The Journal of Neuroscience, October 1, 1998, 18(19):7687-7699

Whole-Cell and Single-Channel Analysis of P-Type Calcium Currents in Cerebellar Purkinje Cells of Leaner Mutant Mice

Leonard S. Dove¹, Louise C. Abbott², and William H. Griffith¹

¹ Department of Medical Pharmacology and Toxicology, College of Medicine, Texas A&M University Health Science Center, College Station, Texas 77843-1114, and ² Department of Veterinary Anatomy and Public Health, College of Veterinary Medicine, Texas A&M University, College Station, Texas 77843-4458

The leaner (tg^la) mutation in mice results in severe ataxia and an overt neurodegeneration of the cerebellum. Positional cloning has revealed that the tg^la mutation occurs in a gene encoding the voltage-activated calcium channel _1A subunit. The _1A subunit is highly expressed in the cerebellum and is thought to be the pore-forming subunit of P- and Q-type calcium channels. In this study we used both whole-cell and single-channel patch-clamp recordings to examine the functional consequences of the tg^la mutation on P-type calcium currents. High-voltage-activated (HVA) calcium currents were recorded from acutely dissociated cerebellar Purkinje cells of homozygous leaner (tg^la/tg^la) and age-matched wild-type (+/+) mice. In whole cell recordings, we observed a marked reduction of peak current density in tg^la/tg^la Purkinje cells (35.0 ± 1.8 pA/pF) relative to that in +/+ (103.1 ± 5.9 pA/pF). The reduced whole-cell current in tg^la/tg^la cells was accompanied by little to no alteration in the voltage dependence of channel gating. In both genotypes, HVA currents were predominantly of the -agatoxin-IVA-sensitive P-type. Cell-attached patch-clamp recordings revealed no differences in single-channel conductance between the two genotypes and confirmed the presence of three distinct conductance levels (9, 13-14, and 17-18 pS) in cerebellar Purkinje cells. Analysis of patch open-probability (NP_o) revealed a threefold reduction in the open-probability of channels in tg^la/tg^la patches (0.04 ± 0.01) relative to that in +/+ (0.13 ± 0.02), which may account for the reduced whole-cell current in tg^la/tg^la Purkinje cells. These results suggest that the tg^la mutation can alter native P-type calcium channels at the single-channel level and that these alterations may contribute to the neuropathology of the leaner phenotype.

Key words: Purkinje cell; calcium channel; single channel; leaner; neurological mutant; mouse

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Copyright © 1998 Society for Neuroscience  0270-6474/98/18197687-13$05.00/0

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