Knock-in mice expressing an ethanol-resistant GluN2A NMDA receptor subunit show altered responses to ethanol
| Autor: | Paula A. Zamudio, Thetford C. Smothers, Gregg E. Homanics, John J. Woodward |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Male
endocrine system Cerebellum Alcohol Drinking 030508 substance abuse Medicine (miscellaneous) Gene Expression Prefrontal Cortex Mice Transgenic Pharmacology Toxicology Receptors N-Methyl-D-Aspartate Article 03 medical and health sciences Glutamatergic Mice 0302 clinical medicine Organ Culture Techniques Gene knockin mental disorders medicine Extracellular Animals Gene Knock-In Techniques Receptor reproductive and urinary physiology Ethanol Chemistry Motor coordination Mice Inbred C57BL Psychiatry and Mental health Electrophysiology medicine.anatomical_structure nervous system NMDA receptor Female 0305 other medical science 030217 neurology & neurosurgery Locomotion |
| Zdroj: | Alcohol Clin Exp Res |
| Popis: | BACKGROUND: N-methyl-D-aspartate receptors (NMDARs) are glutamate-activated, heterotetrameric ligand-gated ion channels critically important in virtually all aspects of glutamatergic signaling. Ethanol inhibition of NMDARs is thought to mediate specific actions of ethanol during acute and chronic exposure. Studies from our laboratory, and others, identified ethanol-sensitive sites within specific transmembrane (TM) domains involved in channel gating as well as those in sub-domains of extracellular and intracellular regions of GluN1 and GluN2 subunits that affect channel function. In this study, we characterize for the first time the physiological and behavioral effects of ethanol on knock-in mice expressing a GluN2A subunit that shows reduced sensitivity to ethanol. METHODS: A battery of tests evaluating locomotion, anxiety, sedation, motor coordination and voluntary alcohol intake were performed in wild-type mice and those expressing the GluN2A A825W knock-in mutation. Whole-cell patch clamp electrophysiological recordings were used to confirm reduced ethanol sensitivity of NMDAR-mediated currents in two separate brain regions (mPFC and the cerebellum) where the GluN2A subunit is known to contribute to NMDAR-mediated responses. RESULTS: Male and female mice homozygous for the GluN2A(A825W) knock-in mutation showed reduced ethanol inhibition of NMDAR-mediated synaptic currents in mPFC and cerebellar neurons as compared to their wild-type counterparts. GluN2A(A825W) male but not female mice were less sensitive to the sedative and motor-incoordinating effects of ethanol and showed a right-ward shift in locomotor stimulating effects of ethanol. There was no effect of the mutation on ethanol-induced anxiolysis or voluntary ethanol consumption in either male or female mice. CONCLUSIONS: These findings show that expression of ethanol-resistant GluN2A NMDARs results in selective and sex-specific changes in the behavioral sensitivity to ethanol. |
| Databáze: | OpenAIRE |
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