title: GABAergic miniature postsynaptic currents in septal neurons show differential allosteric sensitivity after binge-like ethanol exposure.
abstract: Binge-like ethanol treatment of septal neurons blunts GABAAR-mediated miniature postsynaptic currents (mPSCs), suggesting it arrests synaptic development. Ethanol may disrupt postsynaptic maturation by blunting feedback signaling through immature GABAARs. Here, the impact of ethanol on the sensitivity of mPSCs to zolpidem, zinc and 3alpha-hydroxy-5alpha-pregnan-20-one (3alpha-OH-DHP) was tested. The decay phase of mPSCs showed concentration-dependent potentiation by zolpidem (0.03-100 microM), which was substantially blunted after ethanol exposure. Since zolpidem potentiation exhibited a substantial age-dependent increase in untreated neurons, this finding supported the idea that ethanol arrests synaptic development. GABAAR alpha1 subunit protein also increased with age in untreated neurons, paralleling enhanced sensitivity to zolpidem. Surprisingly, alpha1 levels were not reduced by binge ethanol even though mPSCs were relatively zolpidem-insensitive. Zinc (3-30 microM) decreased mPSC parameters in a concentration- and age-related manner with older untreated cells showing less inhibition. However, there was no increase in mPSC zinc sensitivity after binge ethanol as would be expected if a general arrest of synaptic maturation had occurred. 3alpha-OH-DHP (3-1000 nM) induced concentration-dependent potentiation of mPSC decay. Although potentiation was age-independent, binge ethanol treatment exaggerated sensitivity to this neurosteroid. Finally, chronic picrotoxin pretreatment (100 microM) intended to mimic GABAAR inhibition from ethanol pretreatment did not significantly change mPSC modulation by zolpidem, zinc or 3alpha-OH-DHP. These results suggest that binge ethanol treatment selectively arrests a subset of processes important for maturation of postsynaptic GABAA Rs. However, it is unlikely that ethanol causes a broad arrest of postsynaptic development through a direct inhibition of GABAAR signaling.
authors.affiliation: Department of Neuroscience and Experimental Therapeutics, College of Medicine (ms 1114), Texas A & M System Health Science Center, College Station, TX 77843-1114, USA. ddubois@wfubmc.edu
authors.forename: Dustin W
authors.initials: DW
authors.lastname: DuBois
authors.forename: Jerome P
authors.initials: JP
authors.lastname: Trzeciakowski
authors.forename: Alan R
authors.initials: AR
authors.lastname: Parrish
authors.forename: Gerald D
authors.initials: GD
authors.lastname: Frye
mesh_terms: D000367:Age Factors; D020268:Alcohol-Induced Disorders, Nervous System / Q000378:metabolism* / Q000503:physiopathology; D000494:Allosteric Regulation / Q000187:drug effects / Q000502:physiology; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D002492:Central Nervous System Depressants / Q000008:administration & dosage / Q000009:adverse effects; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004347:Drug Interactions / Q000502:physiology; D000431:Ethanol / Q000008:administration & dosage / Q000009:adverse effects*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D018755:GABA Agonists / Q000494:pharmacology; D018756:GABA Antagonists / Q000494:pharmacology; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D009433:Neural Inhibition / Q000187:drug effects* / Q000502:physiology; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D011963:Receptors, GABA-A / Q000187:drug effects* / Q000378:metabolism; D012686:Septal Nuclei / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology; D015032:Zinc / Q000494:pharmacology; D000077334:Zolpidem
chemical_list: D002492:Central Nervous System Depressants; D018691:Excitatory Amino Acid Antagonists; D018755:GABA Agonists; D018756:GABA Antagonists; D011725:Pyridines; D011963:Receptors, GABA-A; D000431:Ethanol; D000077334:Zolpidem; D015032:Zinc