Neurosteroid administration and withdrawal alter GABAA receptor kinetics in CA1 hippocampus of female rats.
Withdrawal from the GABA-modulatory steroid 3alpha-OH-5alpha-pregnan-20-one (3alpha,5alpha-THP) following exposure of female rats to the parent compound progesterone (P) produces a syndrome characterized by behavioural excitability in association with up-regulation of the alpha4 subunit of the GABA(A) receptor (GABAR) in the hippocampus. Similar changes are seen after 48 h exposure to its stereoisomer, 3alpha,5beta-THP. Here, we further characterize the effects of P withdrawal on GABAR kinetics, using brief (1 ms) application of 5-10 mm GABA to outside-out patches from acutely isolated CA1 hippocampal pyramidal cells. Under control conditions, GABA-gated current deactivated biexponentially, with tau(fast) = 12-19 ms (45-60% of the current), and tau(slow) = 80-140 ms. P withdrawal resulted in marked acceleration of deactivation (tau(fast) = 3-7 ms and tau(slow) = 30-100 ms), as did 48 h exposure to 3alpha,5beta-THP (tau(fast) = 5-8 ms; tau(slow) = 40-120 ms). When recombinant receptors were tested in HEK-293 cells, a similar acceleration in tau(fast) was observed for alpha4beta2delta and alpha4beta2gamma2 GABARs, compared to alpha1beta2gamma2 and alpha5beta2gamma2 receptors. In addition, tau(slow) was also accelerated for alpha4beta2delta receptors, which are increased following steroid withdrawal. As predicted by the Jones-Westbrook model, this change was accompanied by reduced receptor desensitization as well as an acceleration of the rate of recovery from rapid desensitization. A theoretical analysis of the data suggested that steroid treatment leads to receptors with a greater stability of the bound, activatable state. This was achieved by altering multiple parameters, including desensitization and gating rates, within the model. These results suggest that fluctuations in endogenous steroids result in altered GABAR kinetics which may regulate neuronal excitability.
Smith
Sheryl S
SS
Department of Physiology and Pharmacology, SUNY Downstate Medical Center, 450 Clarkson Ave., Brooklyn, NY 11203, USA. sheryl.smith@downstate.edu
Gong
Qi Hua
QH
D000818:Animals; D005260:Female; D058785:GABA-A Receptor Agonists; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D008959:Models, Neurological; D018377:Neurotransmitter Agents / Q000008:administration & dosage; D011374:Progesterone / Q000008:administration & dosage*; D051381:Rats; D020318:Rats, Long-Evans; D011963:Receptors, GABA-A / Q000378:metabolism*; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology
D058785:GABA-A Receptor Agonists; D018377:Neurotransmitter Agents; D011963:Receptors, GABA-A; D011374:Progesterone; D005680:gamma-Aminobutyric Acid