Excitatory/Inhibitory unbalance in Ataxia telangiectasia and perspective therapeutical interventions

Ataxia telangectasia (A-T) is typically a progressive degenerative condition that results in major neurological disability. The frequency of A-T in the United States and Britain has been estimated to be between 1:40,000 and 1:100,000, reflecting a carrier frequency of 0.5-1%. The disorder is caused by mutations in the Atm protein kinase gene and no effective treatments have been found to alter the course of this pathological condition. Neurological manifestations include postural instability of the trunk occurring as early as at 1 year of age, progressive cerebellar ataxia, oculo-cutaneous telangiectasias, dysarthria, high propensity to neural tumors and progressive decline in cognitive performance. The aim of the present study is to explore the hypothesis that mutations in Atm kinase cause the disease by altering specific molecular mechanisms that govern nervous transmission. This hypothesis is based on our preliminary findings that transient reduction of Atm protein expression in hippocampal cultured neurons is responsible for an excitation/inhibition unbalance, a process that can support the progressive decline in cognitive performance observed in clinic. In addition, our preliminary studies in vivo also confirm the in vitro unbalance between excitation and inhibition, thus we aim now at discovering how reduced levels of Atm can impact on cognitive and behavioral performance. To this purpose, we will use an array of modern biochemical, electrophysiological and behavioral approaches. Similarly to humans, the mouse model of A-T exhibits a slowly progressive neurological disorder characterized by ataxia and cerebellar atrophy, and therefore represents a suitable model for studying the biological mechanisms underlying inherited A-T disease. By identifying the primary dysfunctions associated to Atm mutation, we hope to contribute to establishing the rationale for developing an effective therapy for these devastating disorders.