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Regulation of NMDA Receptor Plasticity in the BNST Following Adolescent Alcohol Exposure.

ABSTRACT: Persistent alterations in synaptic plasticity and neurotransmission are thought to underlie the heightened risk of adolescent-onset drinkers to develop alcohol use disorders in adulthood. The bed nucleus of the stria terminalis (BNST) is a compelling region to study the consequences of early alcohol, as it is innervated by cortical structures which undergo continued maturation during adolescence and is critically involved in stress and negative affect-associated relapse. In adult mice, chronic ethanol induces long-term changes in GluN2B-containing NMDA receptors (NMDARs) of the BNST. It remains unclear, however, whether the adolescent BNST is susceptible to such persistent alcohol-induced modifications and, if so, whether they are preserved into adulthood. We therefore examined the short- and long-term consequences of adolescent intermittent ethanol exposure (AIE) on NMDAR transmission and plasticity in the BNST of male and female mice. Whole-cell voltage clamp recordings revealed greater glutamatergic tone in the BNST of AIE-treated males and females relative to air-controls. This change, which corresponded to an increase in presynaptic glutamate release, resulted in altered postsynaptic NMDAR metaplasticity and enhanced GluN2B transmission in males but not females. Only AIE-treated males displayed upregulated GluN2B expression (determined by western blot analysis). While these changes did not persist into adulthood under basal conditions, exposing adult males (but not females) to acute restraint stress reinstated AIE-induced alterations in NMDAR metaplasticity and GluN2B function. These data demonstrate that adolescent alcohol exposure specifically modifies NMDARs in the male BNST, that the plastic changes to NMDARs are long-lasting, and that they can be engaged by stress.

SUBMITTER: Carzoli KL

PROVIDER: S-EPMC6787153 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Regulation of NMDA Receptor Plasticity in the BNST Following Adolescent Alcohol Exposure.

Carzoli Kathryn L KL Sharfman Nathan M NM Lerner Mollie R MR Miller Miriam C MC Holmgren Eleanor B EB Wills Tiffany A TA

Frontiers in cellular neuroscience 20191004

Persistent alterations in synaptic plasticity and neurotransmission are thought to underlie the heightened risk of adolescent-onset drinkers to develop alcohol use disorders in adulthood. The bed nucleus of the stria terminalis (BNST) is a compelling region to study the consequences of early alcohol, as it is innervated by cortical structures which undergo continued maturation during adolescence and is critically involved in stress and negative affect-associated relapse. In adult mice, chronic e ...[more]

PMID: 31636539

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Project description:BackgroundBinge ethanol exposure during adolescence reduces hippocampal neurogenesis, a reduction which persists throughout adulthood despite abstinence. This loss of neurogenesis, indicated by reduced doublecortin+ immunoreactivity (DCX+IR), is paralleled by an increase in hippocampal proinflammatory signaling cascades. As galantamine, a cholinesterase inhibitor, has anti-inflammatory actions, we tested the hypothesis that galantamine would prevent (study 1) or restore (study 2) AIE induction of proinflammatory signals within the hippocampus as well as AIE-induced loss of hippocampal neurogenesis.MethodsGalantamine (4 mg/kg) or vehicle (saline) was administered to Wistar rats during adolescent intermittent ethanol (AIE; 5.0 g/kg ethanol, 2 days on/2 days off, postnatal day [P] 25-54) (study 1, prevention) or after AIE during abstinent maturation to adulthood (study 2, restoration).ResultsResults indicate AIE reduced DCX+IR and induced cleaved caspase3 (Casp3) in DCX-expressing immature neurons. Excitingly, AIE induction of activated Casp3 in DCX-expressing neurons is both prevented and reversed by galantamine treatment, which also resulted in prevention and restoration of neurogenesis (DCX+IR). Similarly, galantamine prevented and/or reversed AIE induction of proinflammatory markers, including the chemokine (C-C motif) ligand 2 (CCL2), cyclooxygenase-2 (COX-2), and high mobility group box 1 (HMGB1) protein, suggesting that AIE induction of proinflammatory signaling mediates both cell death cascades and hippocampal neurogenesis. Interestingly, galantamine treatment increased Ki67+IR generally as well as increased pan-Trk expression specifically in AIE-treated rats but failed to reverse AIE induction of NADPH-oxidase (gp91phox).ConclusionsCollectively, our studies suggest that (1) loss of neurogenesis after AIE is mediated by persistent induction of proinflammatory cascades which drive activation of cell death machinery in immature neurons, and (2) galantamine can prevent and restore AIE disruptions in the hippocampal environmental milieu to then prevent and restore AIE-mediated loss of neurogenesis.

Dataset Information

Regulation of NMDA Receptor Plasticity in the BNST Following Adolescent Alcohol Exposure.

Publications

Regulation of NMDA Receptor Plasticity in the BNST Following Adolescent Alcohol Exposure.

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