Alcohol increases efficacy of immature synapses in a neurosteroid-dependent manner.
Fetal ethanol exposure persistently affects hippocampal circuits leading to learning and memory disabilities. Although the mechanisms responsible for these effects are not fully understood, several studies implicate neurosteroids as mediators of the actions of ethanol. A neurosteroid that appears to be critical for the fetal actions of ethanol is pregnenolone sulfate (PREGS). We found that chronic prenatal ethanol exposure increases PREGS levels in the fetal brain and that an endogenous PREGS-like neurosteroid strengthens excitatory transmission in the neonatal hippocampus. Therefore, we hypothesized that ethanol could affect synaptic transmission in the developing hippocampus in a PREGS-dependent manner. We used patch-clamp electrophysiological techniques and found that 50 mm ethanol strengthens AMPA receptor-mediated transmission in the CA1 region by reducing the failure rate of low-efficacy synapses. This effect was age-dependent and was occluded by application of exogenous PREGS. An anti-PREGS antibody scavenger and blockade of PREGS synthesis prevented the effect of ethanol. These data indicate that the deleterious effects of ethanol on hippocampal development are mediated in part by alterations in neurosteroid production, which results in premature stabilization of excitatory synapses.
Department of Neurosciences, University of New Mexico, HSC, Albuquerque, NM 87131, USA.
Manuel
M
Mameli
C Fernando
CF
Valenzuela
D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D000906:Antibodies / Q000494:pharmacology; D002492:Central Nervous System Depressants / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004558:Electric Stimulation / Q000379:methods; D000431:Ethanol / Q000494:pharmacology*; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D005260:Female; D006624:Hippocampus / Q000166:cytology / Q000254:growth & development*; D066298:In Vitro Techniques; D008297:Male; D009474:Neurons / Q000166:cytology / Q000187:drug effects*; D018408:Patch-Clamp Techniques / Q000379:methods; D011247:Pregnancy; D011284:Pregnenolone / Q000276:immunology / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013569:Synapses / Q000187:drug effects*; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology; D014439:Tyramine / Q000031:analogs & derivatives / Q000494:pharmacology
C103321:4-O-(sulfamoyl)-N-tetradecanoyltyramine; D000906:Antibodies; D002492:Central Nervous System Depressants; C018370:pregnenolone sulfate; D000431:Ethanol; D011284:Pregnenolone; D014439:Tyramine