PMID:25339733

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
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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

References

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