Selective implications of ATM and ATR kinases in hippocampal neurons

ATM and ATR (respectively Ataxia Telangiectasia Mutated, and ATM and Rad3-related) proteins are serine/threonine protein kinases, belonging to the phosphatidylinositol 3-kinase superfamily and known for their role as DNA repair proteins. Indeed, in undifferentiated cells they activate in response to genomic stress, specifically upon double and single strand breaks. Recently, it has been discovered that ATM and ATR play fundamental functions also in postmitotic cells such as neurons, where they participate in the control of synaptic vesicles endocytosis and presynaptic mechanisms for neurotransmitter release. Thus, we decided to investigate how and at which extent ATM and ATR kinases regulate the correct establishment of synaptic plasticity as, according to recent evidence, the proper development of cognitive functions requires the correct functioning of the DNA repair machinery. To address this issue, we treated cultured hippocampal neurons with selective ATM or ATR kinase activity inhibitors both in developing neurons and in more mature cultures. First, we assessed development of the GABAergic system in treated cells as we demonstrated alterations in this process in ATM het and KO hippocampal neurons. Whereas the pharmacological blockade of ATM kinase activity during early postnatal development results in a premature excitatory-to-inhibitory switch of GABA, the pharmacological inhibition of ATR kinase does not affect this step. In mature neurons treated ATM or ATR kinases inhibitors we measured synaptic plasticity by electrophysiology and IF. Both functional electrophysiological and labelling experiments indicate that the induction of long-term potentiation (LTP) by glycine administration is prevented in neurons exposed to the short- or long- lasting treatments with the drugs. Taken together, these results indicate that the kinases activity of both ATM and ATR is fundamental for the normal induction of plasticity processes in mature hippocampal neurons, whereas ATM kinase exclusively controls the proper development of the GABA switch in early postnatal hippocampal cultures.