Journal
CELL DEATH & DISEASE
Volume 13, Issue 7, Pages -Publisher
SPRINGERNATURE
DOI: 10.1038/s41419-022-05038-7
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Funding
- Fondazione Telethon-Italy [GGP16015]
- Ministero della salute Italy [GR-2016-02361366]
- Italian Ministry of University and Research [PRIN 2017B9NCSX, 5C22WM]
- Fondazione Cariplo [2018-0511]
- Brain and Behaviour Research Foundation (NARSAD Young Investigator Grant)
- University of Trento
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In this study, Atm(+/-) and Atm(-/-) mice were used to investigate the effects of the antidepressant Fluoxetine (Fluox) on cognitive defects. The results showed that Fluox specifically increased the levels of NKCC1 in the hippocampus, indicating a context-specificity of ATM. Further analysis revealed increased levels of kainate receptors (KARs) containing Gluk-1 and Gluk-5 subunits in the hippocampus of Atm(+/-) and Atm(-/-) mice. The study suggests that ATM affects both inhibitory and excitatory neurotransmission and may be involved in neurological and psychiatric disorders.
Interest in the function of ataxia-telangiectasia-mutated protein (ATM) is extensively growing as evidenced by preclinical studies that continuously link ATM with new intracellular pathways. Here, we exploited Atm(+/-) and Atm(-/-) mice and demonstrate that cognitive defects are rescued by the delivery of the antidepressant Fluoxetine (Fluox). Fluox increases levels of the chloride intruder NKCC1 exclusively at hippocampal level suggesting an ATM context-specificity. A deeper investigation of synaptic composition unveils increased Gluk-1 and Gluk-5 subunit-containing kainate receptors (KARs) levels in the hippocampus, but not in the cortex, of Atm(+/-) and Atm(-/-) mice. Analysis of postsynaptic fractions and confocal studies indicates that KARs are presynaptic while in vitro and ex vivo electrophysiology that are fully active. These changes are (i) linked to KCC2 activity, as the KCC2 blockade in Atm(+/-) developing neurons results in reduced KARs levels and (ii) developmental regulated. Indeed, the pharmacological inhibition of ATM kinase in adults produces different changes as identified by RNA-seq investigation. Our data display how ATM affects both inhibitory and excitatory neurotransmission, extending its role to a variety of neurological and psychiatric disorders.
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