Neuroscience 2005 Abstract
| Presentation Number: | 262.14 |
|---|---|
| Abstract Title: | Experimental alterations in the function of δ subunit-containing GABA<sub>A</sub>Rs alter seizure susceptibility during the ovarian cycle in mice. |
| Authors: |
Maguire, J. L.*1
; Stell, B. M.1
; Rafizadeh, M.1
; Mody, I.1
1Dept Neurol, Univ. of California, Los Angeles (UCLA), Los Angeles, CA |
| Primary Theme and Topics |
Neural Excitability, Synapses, and Glia: Cellular Mechanisms - Ligand-Gated Ion Channels -- GABAa receptors: Physiology |
| Secondary Theme and Topics | Disorders of the Nervous System<br />- Epilepsy<br />-- Basic mechanisms |
| Session: |
262. GABARs: Subunits and Physiology Poster |
| Presentation Time: | Sunday, November 13, 2005 2:00 PM-3:00 PM |
| Location: | Washington Convention Center - Hall A-C, Board # E6 |
| Keywords: | catamenial epilepsy, PMDD, tonic inhibition, epilepsy |
Many women with epilepsy experience cycle-related increased seizure susceptibility, correlated with low progesterone levels, termed catamenial epilepsy. Recurring fluctuations in the levels of neurosteroids are prime candidates for mediating changes in neuronal excitability over the ovarian cycle, but the precise mechanisms responsible for their actions have yet to be elucidated. Progesterone metabolites are known to be potent modulators of GABAA receptors (GABAARs) and tonic inhibition mediated by δ subunit-containing GABAARs is an important site of action of neurosteroids. We have previously shown that changes in GABAARs δ subunit expression during the estrous cycle in mice accompany cyclic changes in seizure susceptibility and anxiety. The GABAR agonist THIP at low concentrations acts selectively at δ subunit-containing GABAARs to enhance the tonic GABAergic inhibition in dentate gyrus granules cells. When tested for its anticonvulsant activity in vivo against kainic acid-induced seizures, i.p. administration of THIP was much more effective at diestrus when δ subunit-containing GABAARs are highly expressed compared to estrus. Blocking the cyclic increase in GABAAR δ subunit expression at late diestrus, using GABAAR δ subunit antisense mRNA or using GABAAR δ-/- or δ+/- mice, prevented the decreased seizure susceptibility and anxiety levels during diestrus. Our data demonstrate that there are normal regulatory mechanisms controlling expression of GABAARs structure and function over the ovarian cycle and the cyclic increase in GABAAR δ subunit expression plays a key role in controlling neuronal excitability. Dysfunction in these normal regulatory processes may be defective in cyclic-associated neurological disorders, such as catamenial epilepsy or premenstrual dysphoric disorder (PMDD).
Sample Citation:
[Authors]. [Abstract Title]. Program No. XXX.XX. 2005 Neuroscience Meeting Planner. Washington, DC: Society for Neuroscience, 2005. Online.
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