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1.
Addict Biol ; 26(2): e12939, 2021 03.
Article in English | MEDLINE | ID: mdl-32720424

ABSTRACT

Ethanol consumption impairs learning and memory through disturbances of NMDA-type glutamate receptor-dependent synaptic plasticity (long-term depression [LTD] and long-term potentiation [LTP]) in the hippocampus. Recently, we demonstrated that two ethanol binge-like episodes in young adult rats selectively blocked NMDA-LTD in hippocampal slices, increased NMDA receptor sensitivity to a GluN2B subunit antagonist, and induced cognitive deficits. Here, using knockout adult mice, we show that a stress-responsive transcription factor of the heat shock factor family, HSF2, which is involved in the perturbation of brain development induced by ethanol, participates in these processes. In the absence of ethanol, hsf2-/- mice show a selective loss of LTD in the hippocampus, which is associated with an increased sensitivity of NMDA-field excitatory postsynaptic potentials (fEPSPs) to a GluN2B antagonist, compared with wild-type (WT) mice. These results suggest that HSF2 is required for proper glutamatergic synaptic transmission and LTD plasticity. After 1 month of chronic ethanol consumption in a two-bottle choice paradigm, WT mice showed an increase in hippocampal synaptic transmission, an enhanced sensitivity to GluN2B antagonist, and a blockade of LTD. In contrast, such modulation of synaptic transmission and plasticity were absent in hsf2-/- mice. We conclude that HSF2 is an important mediator of both glutamatergic neurotransmission and synaptic plasticity in basal conditions and also mediates ethanol-induced neuroadaptations of the hippocampus network after chronic ethanol intake.


Subject(s)
Ethanol/pharmacology , Heat Shock Transcription Factors/drug effects , Long-Term Potentiation/drug effects , Long-Term Synaptic Depression/drug effects , N-Methylaspartate/drug effects , Adolescent , Adult , Age Factors , Animals , Hippocampus/drug effects , Humans , Mice
2.
Addict Biol ; 25(3): e12760, 2020 05.
Article in English | MEDLINE | ID: mdl-31056842

ABSTRACT

Ethanol (EtOH) induces cognitive impairment through modulation of synaptic plasticity notably in the hippocampus. The cellular mechanism(s) of these EtOH effects may range from synaptic signaling modulation to alterations of the epigenome. Previously, we reported that two binge-like exposures to EtOH (3 g/kg, ip, 9 h apart) in adolescent rats abolished long-term synaptic depression (LTD) in hippocampus slices, induced learning deficits, and increased N-methyl-d-aspartate (NMDA) receptor signaling through its GluN2B subunit after 48 hours. Here, we tested the hypothesis of EtOH-induced epigenetic alterations leading to modulation of GluN2B and GluN2A NMDA receptor subunits. Forty-two days old rats were treated with EtOH or the histone deacetylase inhibitor (HDACi) sodium butyrate (NaB, 600 mg/kg, ip) injected alone or 30 minutes before EtOH. After 48 hours, learning was tested with novel object recognition while synaptic plasticity and the role of GluN2A and GluN2B subunits in NMDA-fEPSP were measured in CA1 field of hippocampus slices. LTD and memory were impaired 48 hours after EtOH and NMDA-fEPSP analysis unraveled changes in the GluN2A/GluN2B balance. These results were associated with an increase in histone deacetylase (HDAC) activity and HDAC2 mRNA and protein while Ac-H4K12 labelling was decreased. EtOH increases expression of HDAC2 and mRNA level for GluN2B subunit (but not GluN2A), while HDAC2 modulates the promoter of the gene encoding GluN2B. Interestingly, NaB pretreatment prevented all the cellular and memory-impairing effects of EtOH. In conclusion, the memory-impairing effects of two binge-like EtOH exposure involve NMDA receptor-dependent LTD deficits due to a GluN2A/GluN2B imbalance resulting from changes in GluN2B expression induced by HDAC2.


Subject(s)
Binge Drinking/genetics , CA1 Region, Hippocampal/drug effects , Central Nervous System Depressants/toxicity , Ethanol/toxicity , Histone Deacetylase 2/drug effects , Long-Term Synaptic Depression/drug effects , Memory/drug effects , Receptors, N-Methyl-D-Aspartate/drug effects , Animals , Binge Drinking/metabolism , Butyric Acid/pharmacology , CA1 Region, Hippocampal/metabolism , Epigenesis, Genetic/drug effects , Excitatory Postsynaptic Potentials/drug effects , Hippocampus/drug effects , Hippocampus/metabolism , Histone Deacetylase 2/genetics , Histone Deacetylase 2/metabolism , Histone Deacetylase Inhibitors/pharmacology , Neuronal Plasticity/drug effects , RNA, Messenger/drug effects , RNA, Messenger/metabolism , Rats , Receptors, N-Methyl-D-Aspartate/genetics , Receptors, N-Methyl-D-Aspartate/metabolism
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