title: Modulation of GABAA receptors in cerebellar granule neurons by ethanol: a review of genetic and electrophysiological studies.
abstract: Cerebellar granule neurons (CGNs) receive inhibitory input from Golgi cells in the form of phasic and tonic currents that are mediated by postsynaptic and extrasynaptic gamma-aminobutyric acid type A (GABAA) receptors, respectively. Extrasynaptic receptors are thought to contain alpha6betaxdelta subunits. Here, we review studies on ethanol (EtOH) modulation of these receptors, which have yielded contradictory results. Although studies with recombinant receptors expressed in Xenopus oocytes indicate that alpha6beta3delta receptors are potently enhanced by acute exposure to low (>or=3 mM) EtOH concentrations, this effect was not observed when these receptors were expressed in Chinese hamster ovary cells. Slice recordings of CGNs have consistently shown that EtOH increases the frequency of phasic spontaneous inhibitory postsynaptic currents (sIPSCs), as well as the tonic current amplitude and noise. However, there is a lack of consensus as to whether EtOH directly acts on extrasynaptic receptors or modulates them indirectly; that is, via an increase in spillover of synaptically released GABA. It was recently demonstrated that an R to Q mutation of amino acid 100 of the alpha6 subunit increases the effect of EtOH on both sIPSCs and tonic current. These electrophysiological findings have not been reproducible in our hands. Moreover, it was shown the alpha6-R100Q mutation enhances sensitivity to the motor-impairing effects of EtOH in outbred Sprague-Dawley rats, but this was not observed in a line of rats selectively bred for high sensitivity to EtOH-induced motor alterations (Alcohol Non-Tolerant rats). We conclude that currently there is insufficient evidence conclusively supporting a direct potentiation of extrasynaptic GABAA receptors following acute EtOH exposure in CGNs.
authors.affiliation: Department of Neurosciences, MSC08 4740, 1 University of New Mexico Health Sciences Center, Albuquerque, NM 87131-0001, USA.
authors.forename: Paolo
authors.initials: P
authors.lastname: Botta
authors.forename: Richard A
authors.initials: RA
authors.lastname: Radcliffe
authors.forename: Mario
authors.initials: M
authors.lastname: Carta
authors.forename: Manuel
authors.initials: M
authors.lastname: Mameli
authors.forename: Erin
authors.initials: E
authors.lastname: Daly
authors.forename: Kirsten L
authors.initials: KL
authors.lastname: Floyd
authors.forename: Richard A
authors.initials: RA
authors.lastname: Deitrich
authors.forename: C Fernando
authors.initials: CF
authors.lastname: Valenzuela
mesh_terms: D000818:Animals; D002492:Central Nervous System Depressants / Q000494:pharmacology; D002531:Cerebellum / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D004594:Electrophysiology; D000431:Ethanol / Q000494:pharmacology; D006801:Humans; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D009435:Synaptic Transmission / Q000187:drug effects
chemical_list: D002492:Central Nervous System Depressants; D011963:Receptors, GABA-A; D000431:Ethanol