The Role of ATM in Cerebellar Structure and Function

An aberrant response to DNA lesions is implicated in many human brain degenerative disorders. Various types of DNA lesions activate a cellular process known as the DNA damage response (DDR). Mutations affecting the proteins involved in the DDR can lead to severe genomic instability syndromes, which involve varying degrees of sensitivity to genotoxic stress, and also to tissue degeneration, cancer predisposition, and premature aging. One of the key components of the DDR is the protein ATM, which is inactivated in the genomic instability disorder ataxia-telangiectasia (A-T). When astrocytes and neurons are cultured in vitro, cerebellar networks exhibit spontaneous network events after two weeks. Cerebellar cultures grown from Atm^−/− mice displayed a lower number of global synchronizations and a larger number of sparse synchronizations compared to wild-type cultures. Atm^−/− circuits also had disrupted network synchronization, atrophied astrocytic arborizations, and higher numbers of synapses per neuron than wild-type cultures. Chimeric circuitries composed of wild-type astrocytes and Atm^−/− neurons were indistinguishable from wild-type cultures. Adult cerebellar characterizations confirmed disrupted astrocyte morphology, increased GABAergic synaptic markers, and reduced autophagy in Atm^−/− compared to wild-type mice. Characterizations of adult Atm^−/− cerebella similarly showed disrupted astrocyte morphology, upregulated GABAergic transmission, and dysregulated mTOR-mediated signaling and autophagy. Microglia derived from Atm^−/− mouse cerebellum were severely impaired in phagocytosis, secretion of neurotrophic factors, and mitochondrial activity, an impairment that might imply on an apoptotic process. Interestingly, no microglial impairment was detected in ATM-deficient cerebral cortex. Vascular impairments were detected specifically in the cerebellum but not in the cerebral cortex of Atm^−/− mice. Our findings shed new light on the factors and processes that make the cerebellum so vulnerable to ATM deficiency.