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Increase of KCC2 in hippocampal synaptic plasticity disturbances after perinatal ethanol exposure

Abstract : Low to moderate perinatal ethanol exposure (PEE) may have disastrous consequences for the central nervous system resulting notably in permanent cognitive deficits. Learning and memory are mediated in the hippocampus by long-term potentiation (LTP) and long term depression (LTD), two forms of synaptic plasticity. PEE decreases LTP but also abnormally facilitates LTD (Kervern et al. 2015) through a presently unknown mechanism. We studied in rat hippocampus slice, the involvement of the chloride co-transporters NKCC1 and KCC2, in the role of GABA(A) inhibitions in facilitated LTD after moderate PEE. After PEE and in contrast to control slices, facilitated LTD in CA1 field was reduced by the GABA(A) receptor antagonist bicuculline with no changes in sensitivity to bicuculline and in GABA and benzodiazepine binding sites. Also, sensitivity to diazepam was unaltered, whereas aberrant LTD was blocked. Immunohistochemistry and protein analysis demonstrated an increase in KCC2 protein level at cell membrane in CA1 after PEE with no change in NKCC1 expression. Specifically, both monomeric and dimeric forms of KCC2 were increased in CA1. Bumetanide (10100 mu M), a dose-dependent blocker of NKCC1 and KCC2, or VU0240551 (10 mu M) a specific antagonist of KCC2, corrected the enhanced LTD and interestingly bumetanide also restored the lower LTP after PEE. These results demonstrate for the first time an upregulation of the KCC2 co-transporter expression after moderate PEE associated with disturbances in GABAergic neurotransmission modulating bidirectional synaptic plasticity in the hippocampus. Importantly, bumetanide compensated deficits in both LTP and LTD, revealing its potential therapeutic properties.
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Soumis le : vendredi 25 février 2022 - 17:10:53
Dernière modification le : vendredi 2 septembre 2022 - 14:30:23



Benoit Silvestre De Ferron, Catherine Vilpoux, Myriam Kervern, Alexandre Robert, Johann Antol, et al.. Increase of KCC2 in hippocampal synaptic plasticity disturbances after perinatal ethanol exposure. Addiction Biology, Wiley, 2017, 22 (6), pp.1870-1882. ⟨10.1111/adb.12465⟩. ⟨hal-03589633⟩



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