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.

Atm-deficient mice Purkinje cells show age-dependent defects in calcium spike bursts and calcium currents.

STRATA, Pier Giorgio;TEMPIA, Filippo
2000

Abstract

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.
96
575
583
N. CHIESA; C. BARLOW; A. WYNSHAW-BORIS; P. STRATA; F. TEMPIA
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2318/39994
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