J Neurophysiol (April 1, 2003). 10.1152/jn.00780.2002
Submitted on Submitted 14 August 2002; accepted in final form 18 December 2002

Neurosteroid Effects on GABAergic Synaptic Plasticity in Hippocampus

 ¹Department of Neurobiology and Anatomy, Medical College of Pennsylvania-Hahnemann University, Philadelphia, Pennsylvania 19129; and  ²Department of Physiology and Pharmacology, State University of New York Downstate Medical Center, Brooklyn, New York 11203

Hsu, Fu-Chun, Robert Waldeck, Donald S. Faber, and Sheryl S. Smith. Neurosteroid Effects on GABAergic Synaptic Plasticity in Hippocampus. J. Neurophysiol. 89: 1929-1940, 2003. We have previously reported that short-term (48-72 h) exposure to the GABA-modulatory steroid 3-OH-5-pregnan-20-one (3,5-THP) increases expression of the 4 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 () 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 3,5/-THP (10 mg/kg, ip). Hormone treatment produced a marked acceleration in the fast decay time constant (_fast) of GABAergic mIPSCs. This effect was prevented by suppression of 4-subunit expression with antisense (AS) oligonucleotide, suggesting that hormone treatment increases 4-containing GABAR subsynaptically. This conclusion was further supported by pharmacological data from 3,5-THP-treated animals, demonstrating a bimodal distribution of s for individual mIPSCs following bath application of the 4-selective benzodiazepine RO15-4513, with a shift to slower values. Because 40-50% of the individual s were also shifted to slower values following bath application of the non-4-selective benzodiazepine agonist lorazepam (LZM), we suggest that the number of GABAR synapses containing 4 subunits is equivalent to those that do not following 48-h administration of 3,5-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.