Progesterone Withdrawal Reduces Paired-Pulse Inhibition in Rat Hippocampus: Dependence on GABA_A Receptor α4 Subunit Upregulation

Abstract

Withdrawal from the endogenous steroid progesterone (P) after chronic administration increases anxiety and seizure susceptibility via declining levels of its potent GABA-modulatory metabolite 3alpha-OH-5alpha-pregnan-20-one (3alpha,5alphaTHP). This 3alpha,5alpha-THP withdrawal also results in a decreased decay time constant for GABA-gated current assessed using whole cell patch-clamp techniques on pyramidal cells acutely dissociated from CA1 hippocampus. The purpose of this study was to test the hypothesis that the decreases in total integrated GABA-gated current observed at the level of the isolated pyramidal cell would be manifested as a reduced GABA inhibition at the circuit level following hormone withdrawal. Toward this end, adult, female rats were administered P via subcutaneous capsule for 3 wk using a multiple withdrawal paradigm. We then evaluated paired-pulse inhibition (PPI) of pyramidal neurons in CA1 hippocampus using extracellular recording techniques in hippocampal slices from rats 24 h after removal of the capsule (P withdrawal, P Wd). The population spike (PS) was recorded at the stratum pyramidale following homosynaptic orthodromic stimulation in the nearby stratum radiatum. The threshold for eliciting a response was decreased after P Wd, and the mean PS amplitude was significantly increased compared with control values at this time. Paired pulses with 10-ms inter-pulse intervals were then applied across an intensity range from 2 to 20 times threshold. Evaluation of paired-pulse responses showed a significant 40-50% reduction in PPI for PS recorded in the hippocampal CA1 region after P Wd, suggesting an increase in circuit excitability. At this time, enhancement of PPI by the benzodiazepine lorazepam (LZM; 10 microM) was prevented, while pentobarbital (10 microM) potentiation of PPI was comparable to control levels of response. These data are consistent with upregulation of the alpha4 subunit of the GABA(A) receptor (GABAR) as we have previously shown. Moreover, the reduced PPI caused by P Wd was prevented by suppression of GABAR alpha4-subunit expression following intraventricular administration of specific antisense oligonucleotides (1 microg/h for 72 h). These results demonstrating a reduction in PPI following P Wd suggest that GABAergic-mediated recurrent or feed-forward inhibition occurring at the circuit level were decreased following P Wd in female rats, an effect at least partially attributable to alterations in the GABAR subunit gene expression.

The role of ovarian hormone-derived neurosteroids on the regulation of GABAA receptors in affective disorders

“…Progesterone mediated increases in δ subunit expression were blocked by the 5-α reductase inhibitor finasteride (Maguire et al 2005; Wu et al 2013) but not by the progesterone receptor inhibitor RU489 (mifepristone,(Maguire et al 2005)) or in progesterone receptor KO mice (Wu et al 2013) demonstrating that neurosteroids and not progesterone itself mediate these changes. These results are also mimicked in both progesterone administration and withdrawal models (Griffiths and Lovick 2005a; Gulinello et al 2001; Hsu and Smith 2003; Shen et al 2005) demonstrating that sex steroids and their metabolites modify GABAergic inhibition throughout the estrous cycle by altering the expression of specific GABA A R subunits.…”

GABAergic Neurotransmission in the Premammillary Nucleus of the Turkey Hypothalamus Regulates Reproductive Seasonality and the Onset of Photorefractoriness

“…In this study, termination of breeding activities and the onset of photorefractoriness are associated with an upregulation in the expression of GABA receptors in the PMM. As reported in mammals, the withdrawal of steroid hormones triggers GABAergic inhibition [40,41,42], and this mechanism may hold true for the turkey and other avian species. Diminished circulating ovarian steroids at the end of a laying period could trigger the upregulation of GABA receptors which lead to the advancement of the photorefractory state.…”

Abrupt rather than gradual hormonal changes induce postpartum blues-like behavior in rats

“…Withdrawal of allopregnalone induced an increase of GABA A binding sites, containing particularly α-4 subunits, this correlated with both a decrease in GABA A gated Cl − current as well as anxiety behavior (Bitran and Smith, 2005;Smith et al, 1998a). Blockage or suppression of the expression of the α-4 subunit prevented these changes, emphasizing their role in withdrawal behavior (Hsu and Smith, 2003;Smith et al, 1998a).These observations elucidated the physiology of withdrawal behavior, but do not explain why only a subgroup of women develops postpartum blues. We suggest that differences in the capacity to adapt to the postpartum hormonal changes might be involved in the etiology of postpartum blues.…”