title: HSF1 transcriptional activity mediates alcohol induction of Vamp2 expression and GABA release.
abstract: Many central synapses are highly sensitive to alcohol, and it is now accepted that short-term alterations in synaptic function may lead to longer-term changes in circuit function. The regulation of postsynaptic receptors by alcohol has been well studied, but the mechanisms underlying the effects of alcohol on the presynaptic terminal are relatively unexplored. To identify a pathway by which alcohol regulates neurotransmitter release, we recently investigated the mechanism by which ethanol induces Vamp2, but not Vamp1, in mouse primary cortical cultures. These two genes encode isoforms of synaptobrevin, a vesicular soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) protein required for synaptic vesicle fusion. We found that alcohol activates the transcription factor heat shock factor 1 (HSF1) to induce Vamp2 expression, while Vamp1 mRNA levels remain unaffected. As the Vamp2 gene encodes a SNARE protein, we then investigated whether ethanol exposure and HSF1 transcriptional activity alter neurotransmitter release using electrophysiology. We found that alcohol increased the frequency of γ-aminobutyric acid (GABA)-mediated miniature IPSCs via HSF1, but had no effect on mEPSCs. Overall, these data indicate that alcohol induces HSF1 transcriptional activity to trigger a specific coordinated adaptation in GABAergic presynaptic terminals. This mechanism could explain some of the changes in synaptic function that occur soon after alcohol exposure, and may underlie some of the more enduring effects of chronic alcohol intake on local circuit function.
authors.affiliation: Department of Neuroscience, Columbia University New York City, NY, USA ; Department of Anesthesiology, Columbia University New York City, NY, USA.
authors.forename: Florence P
authors.initials: FP
authors.lastname: Varodayan
authors.affiliation: Department of Anesthesiology, Columbia University New York City, NY, USA ; Department of Pharmacology, Columbia University New York City, NY, USA.
authors.forename: Neil L
authors.initials: NL
authors.lastname: Harrison
keywords: alcohol/ethanol; heat shock factor 1 (HSF1); soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE); synaptobrevin/vesicle-associated membrane protein (VAMP); γ-aminobutyric acid (GABA)