title: Neurosteroid effects on GABAergic synaptic plasticity in hippocampus.
abstract: We have previously reported that short-term (48-72 h) exposure to the GABA-modulatory steroid 3alpha-OH-5alpha-pregnan-20-one (3alpha,5alpha-THP) increases expression of the alpha4 subunit of the GABA(A) receptor (GABAR) in the hippocampus of adult rats. This change in subunit composition was accompanied by altered pharmacology and an increase in general excitability associated with acceleration of the decay time constant (tau) for GABA-gated current of pyramidal cells acutely isolated from CA1 hippocampus similar to what we have reported following withdrawal from the steroid after chronic long-term administration. Because GABAR can be localized to either synaptic or extrasynaptic sites, we tested the hypothesis that this change in receptor kinetics is mediated by synaptic GABAR. To this end, we evaluated the decay kinetics of TTX-resistant miniature inhibitory postsynaptic currents (mIPSCs) recorded from CA1 pyramidal cells in hippocampal slices following 48-h treatment with 3alpha,5alpha/beta-THP (10 mg/kg, ip). Hormone treatment produced a marked acceleration in the fast decay time constant (tau(fast)) of GABAergic mIPSCs. This effect was prevented by suppression of alpha4-subunit expression with antisense (AS) oligonucleotide, suggesting that hormone treatment increases alpha4-containing GABAR subsynaptically. This conclusion was further supported by pharmacological data from 3alpha,5beta-THP-treated animals, demonstrating a bimodal distribution of taus for individual mIPSCs following bath application of the alpha4-selective benzodiazepine RO15-4513, with a shift to slower values. Because 40-50% of the individual taus were also shifted to slower values following bath application of the non-alpha4-selective benzodiazepine agonist lorazepam (LZM), we suggest that the number of GABAR synapses containing alpha4 subunits is equivalent to those that do not following 48-h administration of 3alpha,5beta-THP. The decrease in GABAR-mediated charge transfer resulting from accelerated current decay may then result in increased excitability of the hippocampal circuitry, an effect consistent with the increased behavioral excitability we have previously demonstrated.
authors.affiliation: Department of Neurobiology and Anatomy, Medical College of Pennsylvania-Hahnemann University, Philadelphia, Pennsylvania 19129, USA.
authors.forename: Fu-Chun
authors.initials: FC
authors.lastname: Hsu
authors.forename: Robert
authors.initials: R
authors.lastname: Waldeck
authors.forename: Donald S
authors.initials: DS
authors.lastname: Faber
authors.forename: Sheryl S
authors.initials: SS
authors.lastname: Smith
mesh_terms: D000345:Affinity Labels / Q000494:pharmacology; D000818:Animals; D001386:Azides / Q000494:pharmacology; D001569:Benzodiazepines / Q000494:pharmacology; D005260:Female; D006624:Hippocampus / Q000187:drug effects* / Q000502:physiology*; D009433:Neural Inhibition / Q000187:drug effects; D009473:Neuronal Plasticity / Q000187:drug effects*; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D009924:Organ Culture Techniques; D011280:Pregnanolone / Q000494:pharmacology*; D051381:Rats; D020318:Rats, Long-Evans; D018079:Receptors, GABA / Q000235:genetics / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects; D005680:gamma-Aminobutyric Acid / Q000502:physiology*
chemical_list: D000345:Affinity Labels; D001386:Azides; D016376:Oligonucleotides, Antisense; D018079:Receptors, GABA; D001569:Benzodiazepines; D005680:gamma-Aminobutyric Acid; C042957:Ro 15-4513; D011280:Pregnanolone