Critically timed ethanol exposure reduces GABAAR function on septal neurons developing in vivo but not in vitro.
Six-day 'binge' ethanol intoxication postnatal days (PD) 4-9 delays up-regulation of gamma-aminobutyric acid type A receptors (GABAARs) in developing rat septal neurons [Dev. Brain Res. 130 (2001) 25]. This distortion occurs during synaptogenesis and could contribute to cognitive dysfunction in fetal alcohol syndrome (FAS). Here, we asked two questions concerning requirements for vulnerability to GABAAR blunting by ethanol. First, we asked whether receptor blunting required PD 4-9 ethanol exposure in rat pups and found that just a brief 2-day exposure (PD 8-9) was as effective as all 6 days. However, 2-day exposure on PD 4-5 was ineffective, showing that 'binge' timing was important. We also asked whether 'binge' exposure directly inhibited intrinsic processes of septal neurons and could blunt GABAARs on cells maturing outside the brain. Embryonic septal neurons grown in serum-free dispersed culture developed extensive dendritic arborizations, spontaneous synaptic activity and robust whole-cell GABAAR function, but surprisingly, did not show developmental up-regulation of GABAARs like septal neurons maturing in vivo [Brain Res. 810 (1998) 100]. Furthermore, age-matched 6-day 'binge' ethanol exposure did not blunt GABAAR function in septal neurons in vitro. These results suggest developmental mechanisms driving up-regulation of GABAAR function in septal neurons in vivo briefly becomes vulnerable to ethanol insult in early postnatal life. While septal neurons express comparable functional GABAARs whether maturing in vivo or in vitro, vulnerability to ethanol-induced receptor blunting requires elements of an intact brain environment not replicated in culture.
Hsiao
Shu-Huei
SH
Department of Medical Pharmacology and Toxicology, Texas A&M University System Health Science Center, College Station, TX 77843-1114, USA.
DuBois
Dustin W
DW
Miranda
Rajesh C
RC
Frye
Gerald D
GD
D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D000927:Anticonvulsants / Q000494:pharmacology; D001640:Bicuculline / Q000494:pharmacology; D001835:Body Weight / Q000187:drug effects; D002478:Cells, Cultured; D002492:Central Nervous System Depressants / Q000008:administration & dosage* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004347:Drug Interactions; D004622:Embryo, Mammalian; D000431:Ethanol / Q000008:administration & dosage* / Q000097:blood / Q000494:pharmacology; D005260:Female; D018755:GABA Agonists / Q000494:pharmacology; D018756:GABA Antagonists / Q000494:pharmacology; D018757:GABA Modulators / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D018408:Patch-Clamp Techniques / Q000379:methods; D010406:Penicillins / Q000494:pharmacology; D010852:Picrotoxin / Q000494:pharmacology; D011247:Pregnancy; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000187:drug effects / Q000502:physiology*; D020665:Septum of Brain / Q000166:cytology*; D013307:Streptomycin / Q000494:pharmacology; D013997:Time Factors; D014230:Triazoles / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects; D015032:Zinc / Q000494:pharmacology; D000077334:Zolpidem; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology
D000927:Anticonvulsants; D001640:Bicuculline; D002492:Central Nervous System Depressants; D000431:Ethanol; D018755:GABA Agonists; D018756:GABA Antagonists; D018757:GABA Modulators; D010406:Penicillins; D010852:Picrotoxin; D011500:Protein Synthesis Inhibitors; D011725:Pyridines; D011963:Receptors, GABA-A; D013307:Streptomycin; D014230:Triazoles; D015032:Zinc; D000077334:Zolpidem; D005680:gamma-Aminobutyric Acid; C066440:loreclezole