Journal
NEUROSCIENCE
Volume 96, Issue 3, Pages 575-583Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/S0306-4522(99)00581-3
Keywords
Atm-deficient; calcium; cerebellum; mouse; Purkinje cell
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Ataxia telangiectasia in humans results from homozygous loss-of-function mutations in ATM. Neurological deterioration is the major cause of death in ataxia telangiectasia patients: in the cerebellum, mainly Purkinje cells are affected. We have generated Atm-deficient mice which display neurological abnormalities by several tests of motor function consistent with an abnormality of cerebellar function, but without histological evidence of neuronal degeneration. Here we performed a more detailed morphological analysis and an electrophysiological study on Purkinje cells from Atm-deficient mice of different ages. We found no histological or immunohistochemical abnormalities. Electrophysiology revealed no abnormalities in resting membrane potential, input resistance or anomalous rectification. In contrast, there was a significant decrease in the duration of calcium and sodium firing. The calcium deficit became significant between six to eight and 12-20 weeks of age, and appeared to be progressive. By voltage-clamp recording, we found that the firing deficits were due to a significant decrease in calcium currents, while inactivating: potassium currents seem unaffected. In other mutant mice, calcium current deficits have been shown to be related to cell death. Our experiments suggest that the electrophysiological defects displayed by Atm-deficient mice are early predegenerative lesions and may be a precursor of Purkinje cell degeneration displayed by ataxia telangiectasia patients. (C) 2000 IBRO. Published by Elsevier Science Ltd.
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