Abstract
Gamma (γ) oscillations (30–120 Hz), an emergent property of neuronal networks, correlate with memory, cognition and encoding. In the hippocampal CA3 region, locally generated γ oscillations emerge through feedback between inhibitory parvalbumin-positive basket cells (PV+BCs) and the principal (pyramidal) cells. PV+BCs express δ-subunit-containing GABAARs (δ-GABAARs) and NMDA receptors (NMDA-Rs) that balance the frequency of γ oscillations. Neuroactive steroids (NS), such as the progesterone-derived (3α,5α)-3-hydroxy-pregnan-20-one (allopregnanolone; ALLO), modulate the expression of δ-GABAARs and the tonic conductance they mediate. Pregnancy produces large increases in ALLO and brain-region-specific homeostatic changes in δ-GABAARs expression. Here we show that in CA3, where most PV+ interneurons (INs) express δ-GABAARs, expression of δ-GABAARs 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 γ 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 γ 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 γ oscillatory activity through direct effects on the GABAergic system, and underscore the importance of δ-GABAARs homeostatic plasticity in maintaining constant network output despite large hormonal changes. Inaccurate coupling of NS levels to δ-GABAAR 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.
Highlights
Oscillations in cortical local field potentials in the γ-frequency band (30–120 Hz) reflect coordinated neuronal activity that manifests during different processing tasks such as memory and sensory encoding, and are considered important in adaptive functional organization of neuronal assemblies, spike-time dependent synaptic plasticity, and neurological performance (Singer, 1993; Paulsen and Moser, 1998; Sederberg et al, 2003; Montgomery and Buzsáki, 2007).Frequency and power of γ oscillations result from a synchronized feedback dialogue between excitatory neurons and perisomatic inhibitory interneurons (INs)
We have previously proposed a model for δ-GABAARs downregulation in excitatory neurons as a homeostatic mechanism of adaptation that allows these cells to maintain a constant level of excitability throughout pregnancy (Maguire et al, 2009)
CONCLUDING REMARKS We have demonstrated a homeostatic down-regulation of δGABAARs in PV+ INs in late pregnancy
Summary
Oscillations in cortical local field potentials in the γ-frequency band (30–120 Hz) reflect coordinated neuronal activity that manifests during different processing tasks such as memory and sensory encoding, and are considered important in adaptive functional organization of neuronal assemblies, spike-time dependent synaptic plasticity, and neurological performance (Singer, 1993; Paulsen and Moser, 1998; Sederberg et al, 2003; Montgomery and Buzsáki, 2007).Frequency and power of γ oscillations result from a synchronized feedback dialogue between excitatory neurons and perisomatic inhibitory interneurons (INs). We have previously shown how γ oscillation frequency recorded in the CA3 in vitro is controlled by a δ-GABAARs-mediated tonic conductance of INs, that is dynamically balanced by an NMDA-R-mediated tonic excitation (Mann and Mody, 2010). Synaptic GABAARs-mediated phasic counterpart, tonic inhibition is a slow persistent inhibitory conductance that is activated by ambient GABA, is mediated by extrasynaptic GABAARs, and decreases overall neuronal excitability by hyperpolarization or shunting inhibition (Brickley and Mody, 2012). Regardless of cell specificity, all δ-GABAARs are uniquely sensitive to NS, including the progesterone-derived ALLO. NS can modulate network excitability by modifying δ-GABAARs surface expression (Maguire et al, 2005; Maguire and Mody, 2007), albeit candidate molecular mechanisms remain unknown. Brain ALLO follows oscillations in plasma progesterone, and during the last third of pregnancy, they both reach concentrations two orders of magnitude higher than any other physiological state
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