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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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PV distribution remains unchanged throughout the different gestational states. (A) Representative bright-field images of whole hippocampal DAB staining for PV in virgin, pregnant and postpartum WT mice. PV+ terminals innervate CA1 and CA3 pyramidal cells and dentate gyrus granule cells, and form a plexus that wraps around their somata and proximal dendrites. (B) Representative high-magnification images of CA3 PV plexus in virgin, pregnant and postpartum WT mice. PV+IN somata are clearly visible within the stratum pyramidale (SP) and in its immediate vicinity (initial portion of stratum oriens SO and stratum lucidum SL), arrowheads. Optical density measurements in CA3 SP show no difference across gestational groups (in arbitrary units AU, mean ± SEM: virgin = 193.6 ± 0.9; pregnant = 192.9 ± 1.9; postpartum = 196.1 ± 1.7; n = 12, 10, 8 slices and n = 3 mice for each group.). One-Way ANOVA; p = 0.32, F(2, 27) = 1.175.
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Figure 1: PV distribution remains unchanged throughout the different gestational states. (A) Representative bright-field images of whole hippocampal DAB staining for PV in virgin, pregnant and postpartum WT mice. PV+ terminals innervate CA1 and CA3 pyramidal cells and dentate gyrus granule cells, and form a plexus that wraps around their somata and proximal dendrites. (B) Representative high-magnification images of CA3 PV plexus in virgin, pregnant and postpartum WT mice. PV+IN somata are clearly visible within the stratum pyramidale (SP) and in its immediate vicinity (initial portion of stratum oriens SO and stratum lucidum SL), arrowheads. Optical density measurements in CA3 SP show no difference across gestational groups (in arbitrary units AU, mean ± SEM: virgin = 193.6 ± 0.9; pregnant = 192.9 ± 1.9; postpartum = 196.1 ± 1.7; n = 12, 10, 8 slices and n = 3 mice for each group.). One-Way ANOVA; p = 0.32, F(2, 27) = 1.175.

Mentions: Immunohistochemistry of immunoperoxidase staining for PV shows numerous PV immunopositive cell bodies and dense terminals surrounding the principal cells in hippocampal areas CA1, DG and CA3, consistent with previously reported distribution of PV staining in these structures (Figure 1A) (Gao and Fritschy, 1994; Freund and Buzsaki, 1996). CA3 PV immunoreactivity is preserved across the three experimental gestational groups. In order to assess potential changes specifically in PV+BCs innervation we carried out a densitometric analysis of PV staining in the SP, an area where most PV+ boutons belong to PV+BCs (Klausberger and Somogyi, 2008). No modification in CA3 PV plexus was detected through optical density (OD) measurements of CA3 SP (Figures 1B, 5).


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)

PV distribution remains unchanged throughout the different gestational states. (A) Representative bright-field images of whole hippocampal DAB staining for PV in virgin, pregnant and postpartum WT mice. PV+ terminals innervate CA1 and CA3 pyramidal cells and dentate gyrus granule cells, and form a plexus that wraps around their somata and proximal dendrites. (B) Representative high-magnification images of CA3 PV plexus in virgin, pregnant and postpartum WT mice. PV+IN somata are clearly visible within the stratum pyramidale (SP) and in its immediate vicinity (initial portion of stratum oriens SO and stratum lucidum SL), arrowheads. Optical density measurements in CA3 SP show no difference across gestational groups (in arbitrary units AU, mean ± SEM: virgin = 193.6 ± 0.9; pregnant = 192.9 ± 1.9; postpartum = 196.1 ± 1.7; n = 12, 10, 8 slices and n = 3 mice for each group.). One-Way ANOVA; p = 0.32, F(2, 27) = 1.175.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 1: PV distribution remains unchanged throughout the different gestational states. (A) Representative bright-field images of whole hippocampal DAB staining for PV in virgin, pregnant and postpartum WT mice. PV+ terminals innervate CA1 and CA3 pyramidal cells and dentate gyrus granule cells, and form a plexus that wraps around their somata and proximal dendrites. (B) Representative high-magnification images of CA3 PV plexus in virgin, pregnant and postpartum WT mice. PV+IN somata are clearly visible within the stratum pyramidale (SP) and in its immediate vicinity (initial portion of stratum oriens SO and stratum lucidum SL), arrowheads. Optical density measurements in CA3 SP show no difference across gestational groups (in arbitrary units AU, mean ± SEM: virgin = 193.6 ± 0.9; pregnant = 192.9 ± 1.9; postpartum = 196.1 ± 1.7; n = 12, 10, 8 slices and n = 3 mice for each group.). One-Way ANOVA; p = 0.32, F(2, 27) = 1.175.
Mentions: Immunohistochemistry of immunoperoxidase staining for PV shows numerous PV immunopositive cell bodies and dense terminals surrounding the principal cells in hippocampal areas CA1, DG and CA3, consistent with previously reported distribution of PV staining in these structures (Figure 1A) (Gao and Fritschy, 1994; Freund and Buzsaki, 1996). CA3 PV immunoreactivity is preserved across the three experimental gestational groups. In order to assess potential changes specifically in PV+BCs innervation we carried out a densitometric analysis of PV staining in the SP, an area where most PV+ boutons belong to PV+BCs (Klausberger and Somogyi, 2008). No modification in CA3 PV plexus was detected through optical density (OD) measurements of CA3 SP (Figures 1B, 5).

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