SELECTIVE LOSS OF DOPAMINERGIC NIGRO-STRIATAL NEURONS IN BRAINS OF ATM-DEFICIENT MICE

Ataxia-telangiectasia (AT) is a human disease caused by mutations in t he ATM gene. The neural phenotype of AT includes progressive cerebella r neurodegeneration, which results in ataxia and eventual motor dysfun ction, Surprisingly, mice in which the Atm gene has been inactivated l ack distinct behavioral ataxia or pronounced cerebellar degeneration, the hallmarks of the human disease, To determine whether lack of the A tm protein can nonetheless lead to structural abnormalities in the bra in, we compared brains from male Atm-deficient mice with male, age-mat ched controls. Atm-deficient mice exhibited severe degeneration of tyr osine hydroxylase-positive, dopaminergic nigro-striatal neurons, and t heir terminals in the striatum. This cell loss was accompanied by a la rge reduction in immunoreactivity for the dopamine transporter in the striatum, A reduction in dopaminergic neurons also was evident in the ventral tegmental area. This effect was selective in that the noradren ergic nucleus locus coeruleus was normal in these mice. Behaviorally, Atm-deficient mice expressed locomotor abnormalities manifested as str ide-length asymmetry, which could be corrected by peripheral applicati on of the dopaminergic precursor L-dopa, In addition, these mice were hypersensitive to the dopamine releasing drug D-amphetamine, These res ults indicate that ATM deficiency can severely affect dopaminergic neu rons in the central nervous system and suggest possible strategies for treating this aspect of the disease.