Role of heat shock transcription factor 2 in the NMDA-dependent neuroplasticity induced by chronic ethanol intake in mouse hippocampus

Addict Biol. 2021 Mar;26(2):e12939. doi: 10.1111/adb.12939. Epub 2020 Jul 27.


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.

Keywords: GluN2A; GluN2B; HSF2; NMDA; ethanol; heat shock factor; hippocampus; synaptic plasticity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Age Factors
  • Animals
  • Ethanol / pharmacology*
  • Heat Shock Transcription Factors / drug effects*
  • Hippocampus / drug effects
  • Humans
  • Long-Term Potentiation / drug effects*
  • Long-Term Synaptic Depression / drug effects*
  • Mice
  • N-Methylaspartate / drug effects*


  • Heat Shock Transcription Factors
  • Ethanol
  • N-Methylaspartate