Disturbances of bidirectional synaptic plasticity in the hippocampus after moderate fetal alcohol exposure in ratS

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Pierrefiche O1, Rabiant K1, Robert A1, Kervern M1, Silvestre de Ferron B1, Alaux-Cantin S1, Antol J1, Naassila M1.

1INSERM ERi24 GRAP – Groupe de Recherche sur l’Alcool et les Pharmacodépendances, Université Picardie Jules Verne, Amiens, France.

Ethanol exposure during developmental plasticity induces irreversible cognitive deficits in offspring that have been linked to lower NMDA-dependent synaptic long-term potentiation (LTP) in the hippocampus. However, both the mechanisms of action of ethanol (EtOH) and whether NMDA-dependent long-term depression (LTD) is also altered remained unclear. We thus recorded and studied the mechanism of action of EtOH onto NMDA-LTD, in CA1 area of acute hippocampus slices of young adult rats exposed to moderate level of EtOH during gestation and lactation periods. We found that NMDA-LTD was facilitated. This aberrant LTD was GluN2B dependent and expression of the GluN2B subunit was increased only in the synaptic compartment, leading to a synaptic origin of such signal. We next analyzed the GABAergic component in aberrant NMDA-LTD and found that the role of GABAA-R was reversed after EtOH since GABAA inhibitions became permissive of NMDA-LTD. The increase in GABAA function was not related to structural changes and sensitivity to antagonist of the GABAA-R. Indeed, we found a higher expression of the chloride co-transporter KCC2 at the membrane level in CA1 pyramidal cells revealing disturbances in chloride homeostasis after perinatal EtOH exposure. Finally aberrant NMDA-LTD was corrected in presence of two different antagonist of KCC2, including bumetanide a diuretic tested at clinical level in psychiatric diseases such as autism or epilepsia, and surprisingly, the lower LTP was also corrected with bumetanide.
In conclusion, these experiments shed new light in the effects and in the mechanisms of perinatal ethanol exposure on synaptic plasticity in the hippocampus since we suggest that EtOH during brain development induces a reorganization of the excitatory synapse and an alteration in chloride homeostasis. Our results with bumetanide open new avenue on future therapeutic testing in fetal alcohol spectrum disorders.