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PMID:25339733

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Citation

Carver, CM, Wu, X, Gangisetty, O and Reddy, DS (2014) Perimenstrual-like hormonal regulation of extrasynaptic δ-containing GABAA receptors mediating tonic inhibition and neurosteroid sensitivity. J. Neurosci. 34:14181-97

Abstract

Neurosteroids are endogenous regulators of neuronal excitability and seizure susceptibility. Neurosteroids, such as allopregnanolone (AP; 3α-hydroxy-5α-pregnan-20-one), exhibit enhanced anticonvulsant activity in perimenstrual catamenial epilepsy, a neuroendocrine condition in which seizures are clustered around the menstrual period associated with neurosteroid withdrawal (NSW). However, the molecular mechanisms underlying such enhanced neurosteroid sensitivity remain unclear. Neurosteroids are allosteric modulators of both synaptic (αβγ2-containing) and extrasynaptic (αβδ-containing) GABAA receptors, but they display greater sensitivity toward δ-subunit receptors in dentate gyrus granule cells (DGGCs). Here we report a novel plasticity of extrasynaptic δ-containing GABAA receptors in the dentate gyrus in a mouse perimenstrual-like model of NSW. In molecular and immunofluorescence studies, a significant increase occurred in δ subunits, but not α1, α2, β2, and γ2 subunits, in the dentate gyrus of NSW mice. Electrophysiological studies confirmed enhanced sensitivity to AP potentiation of GABA-gated currents in DGGCs, but not in CA1 pyramidal cells, in NSW animals. AP produced a greater potentiation of tonic currents in DGGCs of NSW animals, and such enhanced AP sensitivity was not evident in δ-subunit knock-out mice subjected to a similar withdrawal paradigm. In behavioral studies, mice undergoing NSW exhibited enhanced seizure susceptibility to hippocampus kindling. AP has enhanced anticonvulsant effects in fully kindled wild-type mice, but not δ-subunit knock-out mice, undergoing NSW-induced seizures, confirming δ-linked neurosteroid sensitivity. These results indicate that perimenstrual NSW is associated with striking upregulation of extrasynaptic, δ-containing GABAA receptors that mediate tonic inhibition and neurosteroid sensitivity in the dentate gyrus. These findings may represent a molecular rationale for neurosteroid therapy of catamenial epilepsy.

Links

PubMed PMC4205546 Online version:10.1523/JNEUROSCI.0596-14.2014

Keywords

Animals; Female; Hippocampus/physiology; Menstrual Cycle/physiology; Mice; Mice, Inbred C57BL; Mice, Knockout; Neural Inhibition/physiology; Neurotransmitter Agents/physiology; Organ Culture Techniques; Receptors, GABA-A/physiology; Synapses/physiology

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

MOUSE:GABR1

GO:0030424: axon

ECO:0000314:

C

Staining the antibody showed broad distribution of delta subunits (δ subunit) on the axon. Immunohistochemical distribution of delta subunit in hippocampal CA1 neurons top portion of figure 3 (referred to as 3A in text). GABA (uniprotID: Q9WV18). Mus musculus

complete
CACAO 12289

MOUSE:GABR1

GO:0043025: neuronal cell body

ECO:0000314:

C

Staining the antibody showed broad distribution of delta subunits (δ subunit) on the soma. Immunohistochemical distribution of delta subunit in hippocampal CA1 neurons top portion of figure 3 (referred to as figure 3A within paper). GABA (uniprotID: Q9WV18). Mus musculus

complete
CACAO 12290

MOUSE:GABR1

GO:0030425: dendrite

ECO:0000314:

C

Staining the antibody showed broad distribution of delta subunits (δ subunit) on dendritic regions. Immunohistochemical distribution of delta subunit in hippocampal CA1 neurons top portion of figure 3 (referred to as figure 3A within paper). GABA (uniprotID: Q9WV18). Mus musculus

complete
CACAO 12291

MOUSE:GBRD

GO:0051932: synaptic transmission, GABAergic

ECO:0000314:

P

Figure 2 & 7, up-regulation of protein conferring sensitivity of synaptic activity

complete
CACAO 12241

MOUSE:GBRD

GO:0030424: axon

ECO:0000314:

C

Staining the antibody showed broad distribution of delta subunits (δ subunit) on the axon. Immunohistochemical distribution of delta subunit in hippocampal CA1 neurons top portion of figure 3 (referred to as 3A in text). From UniProt: GABA(A) (uniprotID: P22933). Mus musculus

complete
CACAO 12394

MOUSE:GBRD

GO:0030425: dendrite

ECO:0000314:

C

Staining the antibody showed broad distribution of delta subunits (δ subunit) on dendritic regions. Immunohistochemical distribution of delta subunit in hippocampal CA1 neurons top portion of figure 3 (referred to as figure 3A within paper). From UniProt: GABA(A) (uniprotID: P22933). Mus musculus

complete
CACAO 12395

MOUSE:GBRD

GO:0043025: neuronal cell body

ECO:0000314:

C

Staining the antibody showed broad distribution of delta subunits (δ subunit) on the soma. Immunohistochemical distribution of delta subunit in hippocampal CA1 neurons top portion of figure 3 (referred to as figure 3A within paper). From UniProt: GABA(A) (uniprotID: P22933). Mus musculus

complete
CACAO 12396

MOUSE:CAH1

GO:0030424: axon

ECO:0000314:

C

Staining the antibody showed broad distribution of delta subunits on the axon. Immunohistochemical distribution of delta subunit in hippocampal CA1 neurons top portion of figure 3 (referred to as 3A in text). CA1 (uniprotID: P13634). Mus musculus

complete
CACAO 12272

MOUSE:CAH1

GO:0043025: neuronal cell body

ECO:0000314:

C

Staining the antibody showed broad distribution of delta subunits on the Soma. Immunohistochemical distribution of delta subunit in hippocampal CA1 neurons top portion of figure 3 (referred to as Figure 3A). CA1 (uniprotID: P13634). Mus musculus

complete
CACAO 12273

MOUSE:CAH1

GO:0030425: dendrite

ECO:0000314:

C

Staining the antibody showed broad distribution of delta subunits on the dendritic regions. Immunohistochemical distribution of delta subunit in hippocampal CA1 neurons top portion of figure 3 (referred to as figure 3A in paper). CA1 (uniprotID: P13634). Mus musculus

complete
CACAO 12275

Notes

See also

References

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