Altered gamma oscillations during pregnancy through loss of δ subunit-containing GABAA receptors on parvalbumin interneurons

Gamma (gamma) oscillations (30-120 Hz), an emergent property of neuronal networks, correlate with memory, cognition and encoding. In the hippocampal CA3 region, locally generated gamma oscillations emerge through feedback between inhibitory parvalbumin-positive basket cells (PV+BCs) and the principal (pyramidal) cells. PV+BCs express delta-subunit-containing GABA(A)Rs (delta-GABA(A)Rs) and NMDA receptors (NMDA-Rs) that balance the frequency of gamma oscillations. Neuroactive steroids (NS), such as the progesterone-derived (3 alpha,5 alpha)-3-hydroxy-pregnan-20-one (allopregnanolone; ALLO), modulate the expression of delta-GABA(A)Rs and the tonic conductance they mediate. Pregnancy produces large increases in ALLO and brain-region-specific homeostatic changes in delta-GABA(A)Rs expression. Here we show that in CA3, where most PV+ interneurons (INs) express delta-GABA(A)Rs, expression of delta-GABA(A)Rs on INs diminishes during pregnancy, but reverts to control levels within 48 h postpartum. These anatomical findings were corroborated by a pregnancy-related increase in the frequency of kainate-induced CA3 gamma oscillations in vitro that could be countered by the NMDA-R antagonists D-AP5 and PPDA. Mimicking the typical hormonal conditions during pregnancy by supplementing 100 nM ALLO lowered the gamma frequencies to levels found in virgin or postpartum mice. Our findings show that states of altered NS levels (e.g., pregnancy) may provoke perturbations in gamma oscillatory activity through direct effects on the GABAergic system, and underscore the importance of delta-GABA(A)Rs homeostatic plasticity in maintaining constant network output despite large hormonal changes. Inaccurate coupling of NS levels to delta-GABA(A)R expression may facilitate abnormal neurological and psychiatric conditions such as epilepsy, post-partum depression, and post-partum psychosis, thus providing insights into potential new treatments.