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Addict Biol. 2017 Nov;22(6):1870-1882. doi: 10.1111/adb.12465. Epub 2016 Oct 25.

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

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INSERM ERI-24, GRAP, Groupe de Recherche sur l'Alcool et les Pharmacodépendances, Centre Universitaire de Recherche en Santé CHU-Sud, Université Picardie Jules Verne, Amiens, France.


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. ) 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 GABAA inhibitions in facilitated LTD after moderate PEE. After PEE and in contrast to control slices, facilitated LTD in CA1 field was reduced by the GABAA 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 (10-100 μM), a dose-dependent blocker of NKCC1 and KCC2, or VU0240551 (10 μM) 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.


LTD; LTP; chloride co-transporter; ethanol; hippocampus; prenatal

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