Dancing the Delta Shuffle: Neurosteroids Regulate GABAA Receptor Expression

Abstract

Ovarian Cycle-linked Changes in GABA(A) Receptors Mediating Tonic Inhibition Alter Seizure Susceptibility and Anxiety Maguire JL, Stell BM, Rafizadeh M, Mody I Nat Neurosci 2005;8(6):797–804 Disturbances of neuronal excitability changes during the ovarian cycle may elevate seizure frequency in women with catamenial epilepsy and enhance anxiety in premenstrual dysphoric disorder (PMDD). The mechanisms underlying these changes are unknown, but they could result from the effects of fluctuations in progesterone-derived neurosteroids on the brain. Neurosteroids and some anxiolytics share an important site of action: tonic inhibition mediated by δ subunit–containing GABAA receptors ( δGABAA Rs). Here we demonstrate periodic alterations in specific GABAA R subunits during the estrous cycle in mice, causing cyclic changes of tonic inhibition in hippocampal neurons. In late diestrus (high-progesterone phase), enhanced expression of δGABAA Rs increases tonic inhibition, and a reduced neuronal excitability is reflected by diminished seizure susceptibility and anxiety. Eliminating cycling of δGABAA Rs by antisense RNA treatment or gene knockout prevents the lowering of excitability during diestrus. Our findings are consistent with possible deficiencies in regulatory mechanisms controlling normal cycling of δGABAA Rs in individuals with catamenial epilepsy or PMDD. Short-term Steroid Treatment Increases δ GABAA Receptor Subunit Expression in Rat CA1 Hippocampus: Pharmacological and Behavioral Effects Shen H, Gong QH, Yuan M, Smith SS Neuropharmacology 2005;49(5):573–586 In this study, 48-h administration of 3 α-OH-5 β-pregnan-20-one (3 α,5 β-THP) or 17 β-estradiol (E2)+progesterone (P) to female rats increased expression of the δ subunit of the GABAA receptor in CA1 hippocampus. Coexpression of α4 and δ subunits was suggested by an increased response of isolated pyramidal cells to the GABA agonist 4,5,6,7-tetrahydroisoxazolo[5,4- c]pyridin-3-ol (THIP), following 48-h steroid treatment, and nearly complete blockade by 300 μM lanthanum (La3+). Because α4 βδ GABAA receptors are extrasynaptic, we also recorded pharmacologically isolated GABAergic holding current from CA1 hippocampal pyramidal cells in the slice. The La3+-sensitive THIP current, representative of current gated by α4 βδ GABAA receptor, was measurable only following 48-h steroid treatment. In contrast, the bicuculline-sensitive current was not altered by steroid treatment, assessed with or without 200 nM gabazine to block synaptic current. However, 48-h steroid treatment resulted in a tonic current insensitive to the benzodiazepine agonists lorazepam (10 μM) and zolpidem (100 nM). These results suggest that 48-h steroid treatment increases expression of α4 βδ GABAA receptors, which replace the ambient receptor population. Increased anxiolytic effects of THIP were also observed following 48-h steroid treatment. The findings from the present study may be relevant for alterations in mood and benzodiazepine sensitivity reported across the menstrual cycle.