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Altered gamma oscillations during pregnancy through loss of δ subunit-containing GABA(A) receptors on parvalbumin interneurons.

Ferando I, Mody I - Front Neural Circuits (2013)

Bottom Line: Pregnancy produces large increases in ALLO and brain-region-specific homeostatic changes in δ-GABA(A)Rs expression.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-GABA(A)Rs homeostatic plasticity in maintaining constant network output despite large hormonal changes.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology, The David Geffen School of Medicine, University of California Los Angeles, CA 90095-733522, USA.

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 GABA(A)Rs (δ-GABA(A)Rs) 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-GABA(A)Rs and the tonic conductance they mediate. Pregnancy produces large increases in ALLO and brain-region-specific homeostatic changes in δ-GABA(A)Rs expression. Here we show that in CA3, where most PV+ interneurons (INs) express δ-GABA(A)Rs, expression of δ-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 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-GABA(A)Rs homeostatic plasticity in maintaining constant network output despite large hormonal changes. Inaccurate coupling of NS levels to δ-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.

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Blocking neurosteroidogenesis increases γ oscillations frequency in slices from WT mice. (A) Representative 1 s epoch of local field potential oscillations and corresponding Morlet Wavelets in the CA3 region of hippocampal slices obtained from a WT adult male mouse in vehicle (DMSO 0.01%) or in 1 μ M finasteride (after 30 min incubation). (B) Power spectral densities of the same recordings (average of 180 s) for DMSO 0.01% (black) and finasteride (gray). (C) Peak frequencies of γ oscillations recorded in either vehicle or 1 μ M finasteride. The latter have significantly higher peak frequencies. Box plots represent mean, 25th and 75th percentile, and largest and smallest values. Mean peak frequency ± SEM in Hz: DMSO 0.01% = 44.5 ± 0.5, finasteride = 49.1 ± 0.6 p < 0.0001, two-tailed unpaired t-test. Asterisks denote significance (p < 0.05). No differences were found in power at peak frequency, p = 0.5, and total power (30–120 Hz), p = 1. n's for each group are reported in the figure.
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Figure 7: Blocking neurosteroidogenesis increases γ oscillations frequency in slices from WT mice. (A) Representative 1 s epoch of local field potential oscillations and corresponding Morlet Wavelets in the CA3 region of hippocampal slices obtained from a WT adult male mouse in vehicle (DMSO 0.01%) or in 1 μ M finasteride (after 30 min incubation). (B) Power spectral densities of the same recordings (average of 180 s) for DMSO 0.01% (black) and finasteride (gray). (C) Peak frequencies of γ oscillations recorded in either vehicle or 1 μ M finasteride. The latter have significantly higher peak frequencies. Box plots represent mean, 25th and 75th percentile, and largest and smallest values. Mean peak frequency ± SEM in Hz: DMSO 0.01% = 44.5 ± 0.5, finasteride = 49.1 ± 0.6 p < 0.0001, two-tailed unpaired t-test. Asterisks denote significance (p < 0.05). No differences were found in power at peak frequency, p = 0.5, and total power (30–120 Hz), p = 1. n's for each group are reported in the figure.

Mentions: Given the highly lipophilic nature of NS, it was suggested that they may access their binding sites on GABAARs after accumulation and lateral diffusion in the plasma membrane (Chisari et al., 2010). Whether during in vitro preparations of brain slices NS dissolved in plasma membranes are completely washed off remains to be fully established although some evidence would suggest at least partial depletion. Several in vitro experiments using finasteride, an inhibitor of 5α-reductase (a key enzyme in the local NS synthesis pathway), have unveiled the existence of NS synthesis in slices (Belelli and Lambert, 2005). This suggests that NS synthetized prior to the enzymatic block are either degraded or washed off during in vitro incubation. To confirm this depletion in our slices, in a separate set of experiments in slices from WT males we noticed a significant increase in γ oscillation frequency after 30 min of incubation in 1 μ M finasteride compared to slices incubated in vehicle alone (Figure 7). As δ-GABAARs respond poorly to GABA in the absence of NS, this finding is consistent with the wash-out of NS from slices, following pharmacological blockade of local NS synthesis. NS presence in slices likely result from continuous enzymatic conversion of local precursors, namely steroids synthetized de novo from cholesterol (Rupprecht et al., 2010), rather than the in vivo NS still bound to the plasma membrane after slice preparation. Since during pregnancy most of brain ALLO is derived from plasma progesterone (Paul and Purdy, 1992; Concas et al., 1998), it is reasonable to assume that slices incubated in a progesterone- and ALLO-free nACSF will be devoid of the NS levels found in the brains of pregnant mice. Consequently, in vitro brain preparations of pregnant mice will suffer an acute withdrawal of NS from plasma precursors, making synthesis from local precursors the only enzymatic pathway for maintaining NS levels. In support of this idea, we previously published evidence of altered slice excitability in slices from pregnant mice in the absence of physiological pregnancy levels of ALLO (Maguire et al., 2009).


Altered gamma oscillations during pregnancy through loss of δ subunit-containing GABA(A) receptors on parvalbumin interneurons.

Ferando I, Mody I - Front Neural Circuits (2013)

Blocking neurosteroidogenesis increases γ oscillations frequency in slices from WT mice. (A) Representative 1 s epoch of local field potential oscillations and corresponding Morlet Wavelets in the CA3 region of hippocampal slices obtained from a WT adult male mouse in vehicle (DMSO 0.01%) or in 1 μ M finasteride (after 30 min incubation). (B) Power spectral densities of the same recordings (average of 180 s) for DMSO 0.01% (black) and finasteride (gray). (C) Peak frequencies of γ oscillations recorded in either vehicle or 1 μ M finasteride. The latter have significantly higher peak frequencies. Box plots represent mean, 25th and 75th percentile, and largest and smallest values. Mean peak frequency ± SEM in Hz: DMSO 0.01% = 44.5 ± 0.5, finasteride = 49.1 ± 0.6 p < 0.0001, two-tailed unpaired t-test. Asterisks denote significance (p < 0.05). No differences were found in power at peak frequency, p = 0.5, and total power (30–120 Hz), p = 1. n's for each group are reported in the figure.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3775147&req=5

Figure 7: Blocking neurosteroidogenesis increases γ oscillations frequency in slices from WT mice. (A) Representative 1 s epoch of local field potential oscillations and corresponding Morlet Wavelets in the CA3 region of hippocampal slices obtained from a WT adult male mouse in vehicle (DMSO 0.01%) or in 1 μ M finasteride (after 30 min incubation). (B) Power spectral densities of the same recordings (average of 180 s) for DMSO 0.01% (black) and finasteride (gray). (C) Peak frequencies of γ oscillations recorded in either vehicle or 1 μ M finasteride. The latter have significantly higher peak frequencies. Box plots represent mean, 25th and 75th percentile, and largest and smallest values. Mean peak frequency ± SEM in Hz: DMSO 0.01% = 44.5 ± 0.5, finasteride = 49.1 ± 0.6 p < 0.0001, two-tailed unpaired t-test. Asterisks denote significance (p < 0.05). No differences were found in power at peak frequency, p = 0.5, and total power (30–120 Hz), p = 1. n's for each group are reported in the figure.
Mentions: Given the highly lipophilic nature of NS, it was suggested that they may access their binding sites on GABAARs after accumulation and lateral diffusion in the plasma membrane (Chisari et al., 2010). Whether during in vitro preparations of brain slices NS dissolved in plasma membranes are completely washed off remains to be fully established although some evidence would suggest at least partial depletion. Several in vitro experiments using finasteride, an inhibitor of 5α-reductase (a key enzyme in the local NS synthesis pathway), have unveiled the existence of NS synthesis in slices (Belelli and Lambert, 2005). This suggests that NS synthetized prior to the enzymatic block are either degraded or washed off during in vitro incubation. To confirm this depletion in our slices, in a separate set of experiments in slices from WT males we noticed a significant increase in γ oscillation frequency after 30 min of incubation in 1 μ M finasteride compared to slices incubated in vehicle alone (Figure 7). As δ-GABAARs respond poorly to GABA in the absence of NS, this finding is consistent with the wash-out of NS from slices, following pharmacological blockade of local NS synthesis. NS presence in slices likely result from continuous enzymatic conversion of local precursors, namely steroids synthetized de novo from cholesterol (Rupprecht et al., 2010), rather than the in vivo NS still bound to the plasma membrane after slice preparation. Since during pregnancy most of brain ALLO is derived from plasma progesterone (Paul and Purdy, 1992; Concas et al., 1998), it is reasonable to assume that slices incubated in a progesterone- and ALLO-free nACSF will be devoid of the NS levels found in the brains of pregnant mice. Consequently, in vitro brain preparations of pregnant mice will suffer an acute withdrawal of NS from plasma precursors, making synthesis from local precursors the only enzymatic pathway for maintaining NS levels. In support of this idea, we previously published evidence of altered slice excitability in slices from pregnant mice in the absence of physiological pregnancy levels of ALLO (Maguire et al., 2009).

Bottom Line: Pregnancy produces large increases in ALLO and brain-region-specific homeostatic changes in δ-GABA(A)Rs expression.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-GABA(A)Rs homeostatic plasticity in maintaining constant network output despite large hormonal changes.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology, The David Geffen School of Medicine, University of California Los Angeles, CA 90095-733522, USA.

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 GABA(A)Rs (δ-GABA(A)Rs) 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-GABA(A)Rs and the tonic conductance they mediate. Pregnancy produces large increases in ALLO and brain-region-specific homeostatic changes in δ-GABA(A)Rs expression. Here we show that in CA3, where most PV+ interneurons (INs) express δ-GABA(A)Rs, expression of δ-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 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-GABA(A)Rs homeostatic plasticity in maintaining constant network output despite large hormonal changes. Inaccurate coupling of NS levels to δ-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.

Show MeSH
Related in: MedlinePlus