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Loss of Ethanol Inhibition of N ‐Methyl‐D‐Aspartate Receptor‐Mediated Currents and Plasticity of Cerebellar Synapses in Mice Expressing the GluN1(F639A) Subunit
Author(s) -
ZamudioBulcock Paula A.,
Homanics Gregg E.,
Woodward John J.
Publication year - 2018
Publication title -
alcoholism: clinical and experimental research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.267
H-Index - 153
eISSN - 1530-0277
pISSN - 0145-6008
DOI - 10.1111/acer.13597
Subject(s) - nmda receptor , climbing fiber , cerebellum , synaptic plasticity , chemistry , excitatory postsynaptic potential , synapse , glutamatergic , neurotransmission , neuroscience , long term depression , patch clamp , postsynaptic potential , postsynaptic current , stimulation , electrophysiology , glutamate receptor , medicine , cerebellar cortex , receptor , biology , ampa receptor , biochemistry
Background Glutamatergic N ‐methyl‐ d ‐aspartate receptors ( NMDAR s) 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 NMDAR s. 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, NMDAR s 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 PF s and CF s ( PF ‐ LTD ) requires activation of EtOH‐sensitive NMDAR s. In this study, we examined cerebellar NMDA responses and NMDA ‐mediated synaptic plasticity in wild‐type (WT) and GluN1(F639A) mice. Methods Patch‐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. Results Stimulation of CFs evoked robust NMDA ‐mediated excitatory postsynaptic currents (EPSCs) in PC s that were similar in amplitude and kinetics between WT and GluN1(F639A) mice. NMDA ‐mediated CF ‐ PC EPSC s 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 EPSC s in both WT and mutant mice, and this depression was blocked by the NMDA antagonist DL ‐ APV . The synaptic depression of PF ‐ PC EPSC s in WT mice was also blocked by a low concentration of EtOH (10 mM ) that had no effect on plasticity in GluN1(F639A) mice. Conclusions These results demonstrate that inhibition of cerebellar NMDAR s may be a key mechanism by which EtOH affects cerebellar‐dependent behaviors.