ArticleAlcoholism, clinical and experimental research2018
Loss of Ethanol Inhibition of N-Methyl-D-Aspartate Receptor-Mediated Currents and Plasticity of Cerebellar Synapses in Mice Expressing the GluN1(F639A) Subunit.
Article in Alcoholism, clinical and experimental research, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers.
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7 citing papers in PubMed, 11 citations in OpenAlex.
- Chemogenetic Perturbation of the Posterior But Not Anterior Cerebellum Reduces Voluntary Ethanol Consumption.eNeuro · 2023Article
- The positive allosteric modulator of NMDA receptors, GNE-9278, blocks the ethanol-induced decrease of excitability in developing retrosplenial cortex neurons from mice.Neuropsychopharmacology reports · 2023Article
- The escalation in ethanol consumption following chronic intermittent ethanol exposure is blunted in mice expressing ethanol-resistant GluN1 or GluN2A NMDA receptor subunits.Psychopharmacology · 2021Article
- Alcohol and IL-6 Alter Expression of Synaptic Proteins in Cerebellum of Transgenic Mice with Increased Astrocyte Expression of IL-6.Neuroscience · 2020Article
- Knock-in Mice Expressing an Ethanol-Resistant GluN2A NMDA Receptor Subunit Show Altered Responses to Ethanol.Alcoholism, clinical and experimental research · 2020Article
- Alcohol Intoxication and Cognition: Implications on Mechanisms and Therapeutic Strategies.Frontiers in neuroscience · 2020Review
- The Cerebellar GABAHandbook of experimental pharmacology · 2018Article
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Authors and funding
3 authors at 2 institutions in 1 country.
Funding
Abstract
backgroundGlutamatergic N-methyl-d-aspartate receptors (NMDARs) are well known for their sensitivity to ethanol (EtOH) inhibition. However, the specific manner in which EtOH inhibits channel activity and how such inhibition affects neurotransmission, and ultimately behavior, remains unclear. Replacement of phenylalanine 639 with alanine (F639A) in the GluN1 subunit reduces EtOH inhibition of recombinant NMDARs. Mice expressing this subunit show reduced EtOH-induced anxiolysis, blunted locomotor stimulation following low-dose EtOH administration, and faster recovery of motor function after moderate doses of EtOH, suggesting that cerebellar dysfunction may contribute to some of these behaviors. In the mature mouse cerebellum, NMDARs at the cerebellar climbing fiber (CF) to Purkinje cell (PC) synapse are inhibited by low concentrations of EtOH and the long-term depression (LTD) of parallel fiber (PF)-mediated currents induced by concurrent activation of PFs and CFs (PF-LTD) requires activation of EtOH-sensitive NMDARs. In this study, we examined cerebellar NMDA responses and NMDA-mediated synaptic plasticity in wild-type (WT) and GluN1(F639A) mice.
methodsPatch-clamp electrophysiological recordings were performed in acute cerebellar slices from adult WT and GluN1(F639A) mice. NMDAR-mediated currents at the CF-PC synapse and NMDAR-dependent PF-LTD induction were compared for genotype-dependent differences.
resultsStimulation of CFs evoked robust NMDA-mediated excitatory postsynaptic currents (EPSCs) in PCs that were similar in amplitude and kinetics between WT and GluN1(F639A) mice. NMDA-mediated CF-PC EPSCs in WT mice were significantly inhibited by EtOH (50 mM) while those in mutant mice were unaffected. Concurrent stimulation of CF and PF inputs induced synaptic depression of PF-PC EPSCs in both WT and mutant mice, and this depression was blocked by the NMDA antagonist DL-APV. The synaptic depression of PF-PC EPSCs in WT mice was also blocked by a low concentration of EtOH (10 mM) that had no effect on plasticity in GluN1(F639A) mice.
conclusionsThese results demonstrate that inhibition of cerebellar NMDARs may be a key mechanism by which EtOH affects cerebellar-dependent behaviors.
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