Dataset Information

ATM rules neurodevelopment and glutamatergic transmission in the hippocampus but not in the cortex.

ABSTRACT: 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.

SUBMITTER: Focchi E

PROVIDER: S-EPMC9288428 | biostudies-literature | 2022 Jul

REPOSITORIES: biostudies-literature

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ATM rules neurodevelopment and glutamatergic transmission in the hippocampus but not in the cortex.

Focchi Elisa E Cambria Clara C Pizzamiglio Lara L Murru Luca L Pelucchi Silvia S D'Andrea Laura L Piazza Silvano S Mattioni Lorenzo L Passafaro Maria M Marcello Elena E Provenzano Giovanni G Antonucci Flavia F

Cell death & disease 20220716 7

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<sup>+/-</sup> and Atm<sup>-/-</sup> 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 i ...[more]

PMID: 35842432

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Project description:Temporal lobe epilepsy (TLE) is the most common type of focal epilepsy in humans, and is often developed after an initial precipitating brain injury. This form of epilepsy is frequently resistant to pharmacological treatment; therefore, the prevention of TLE is the prospective approach to TLE therapy. The lithium-pilocarpine model in rats replicates some of the main features of TLE in human, including the pathogenic mechanisms of cell damage and epileptogenesis after a primary brain injury. In the present study, we investigated changes in the properties of glutamatergic transmission during the first 3 days after pilocarpine-induced acute seizures in Wistar rats (PILO-rats). Using RT-PCR and electrophysiological techniques, we compared the changes in the temporal cortex (TC) and hippocampus, brain areas differentially affected by seizures. On the first day, we found a transient increase in a ratio of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl d-aspartate (NMDA) receptors in the excitatory synaptic response in pyramidal neurons of the CA1 area of the dorsal hippocampus, but not in the TC. This was accompanied by an increase in the slope of input-output (I/O) curves for fEPSPs recorded in CA1, suggesting an enhanced excitability in AMPARs in this brain area. There was no difference in the AMPA/NMDA ratio in control rats on the third day. We also revealed the alterations in NMDA receptor subunit composition in PILO-rats. The GluN2B/GluN2A mRNA expression ratio increased in the dorsal hippocampus but did not change in the ventral hippocampus or the TC. The kinetics of NMDA-mediated evoked EPSCs in hippocampal neurons was slower in PILO-rats compared with control animals. Ifenprodil, a selective antagonist of GluN2B-containing NMDARs, diminished the area and amplitude of evoked EPSCs in CA1 pyramidal cells more efficiently in PILO-rats compared with control animals. These results demonstrate that PILO-induced seizures lead to more severe alterations in excitatory synaptic transmission in the dorsal hippocampus than in the TC. Seizures affect the relative contribution of AMPA and NMDA receptor conductances in the synaptic response and increase the proportion of GluN2B-containing NMDARs in CA1 pyramidal neurons. These alterations disturb normal circuitry functions in the hippocampus, may cause neuron damage, and may be one of the important pathogenic mechanisms of TLE.

Dataset Information

ATM rules neurodevelopment and glutamatergic transmission in the hippocampus but not in the cortex.

Publications

ATM rules neurodevelopment and glutamatergic transmission in the hippocampus but not in the cortex.

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