Women constitute a majority of the patients with epilepsy, and many of them experience a cyclical exacerbation of seizures related to periodic changes in serum progesterone and estrogen levels during the menstrual cycle. This condition is called catamenial epilepsy. Currently, there are no scientifically tested effective treatments fr catamenial exacerbation. In a multi-center trial of progesterone therapy for catamenial epilepsy failed to show efficacy. We have developed a model of chronic temporal lobe epilepsy in female rats and will use this model to study the effect of prolonged progesterone exposure on excitatory and inhibitory synaptic transmission and on seizure frequency and intensity. Specifically, we will test our hypothesis that a chronic elevation of progesterone in female animals diminishes the anticonvulsant action of progesterone by enhancing AMPA receptor-mediated glutamatergic synaptic transmission and suppressing GABAA receptor mediated synaptic transmission.
In Aim 1, we will determine the impact of progesterone treatment on glutamatergic synaptic transmission on hippocampal principal neurons in naive and epileptic female rats using a combination of patch clamp electrophysiology and analysis of the expression of the AMPA receptor subunits via both biochemical and immunohistochemical techniques.
In Aim 2, we will determine the impact of progesterone treatment on GABAergic synaptic transmission on hippocampal principal neurons of naive and epileptic female rats with a similar combination of techniques as in aim 1.
In Aim 3, we will determine the role of progesterone receptors in progesterone-induced tolerance during progesterone treatment and withdrawal. These studies will provide novel insights into the mechanisms of catamenial epilepsy. These studies could explain the mechanism of failure progesterone therapy for treatment of catamenial epilepsy and potentially identify novel therapeutic targets for the treatment of catamenial exacerbation of seizures.

Public Health Relevance

Women constitute a majority of patients with epilepsy, and many of them experience cyclical exacerbation of seizures related to periodic changes in serum progesterone and estrogen levels during the menstrual cycle (catamenial epilepsy). Currently the biological mechanisms underlying catamenial epilepsy are poorly understood, there are no scientifically tested effective treatments of catamenial exacerbation. A recent multi-center phase III clinical trial with progesterone failed to show effectiveness in treatment of this disorder. Th proposed studies seek to understand the effects of prolonged progesterone exposure on excitatory and inhibitory synaptic transmission, with a long term goal towards novel therapeutic targets for the treatment of catamenial epilepsy.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01NS044370-09
Application #
8723896
Study Section
Clinical Neuroplasticity and Neurotransmitters Study Section (CNNT)
Program Officer
Whittemore, Vicky R
Project Start
Project End
Budget Start
Budget End
Support Year
9
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Virginia
Department
Neurology
Type
Schools of Medicine
DUNS #
City
Charlottesville
State
VA
Country
United States
Zip Code
22904
Sun, Chengsan; Sun, Jianli; Erisir, Alev et al. (2014) Loss of cholecystokinin-containing terminals in temporal lobe epilepsy. Neurobiol Dis 62:44-55
Zanelli, S; Goodkin, H P; Kowalski, S et al. (2014) Impact of transient acute hypoxia on the developing mouse EEG. Neurobiol Dis 68:37-46
Joshi, Suchitra; Keith, Kendra J; Ilyas, Adeel et al. (2013) GABAA receptor membrane insertion rates are specified by their subunit composition. Mol Cell Neurosci 56:201-11
Joshi, Suchitra; Rajasekaran, Karthik; Kapur, Jaideep (2013) GABAergic transmission in temporal lobe epilepsy: the role of neurosteroids. Exp Neurol 244:36-42
Joshi, Suchitra; Kapur, Jaideep (2013) N-methyl-D-aspartic acid receptor activation downregulates expression of ? subunit-containing GABAA receptors in cultured hippocampal neurons. Mol Pharmacol 84:1-11
Joshi, Suchitra; Sun, Chengsan; Kapur, Jaideep (2011) A mouse monoclonal antibody against the ýý2 subunit of GABAA receptors. Hybridoma (Larchmt) 30:537-42
Rannals, Matthew D; Kapur, Jaideep (2011) Homeostatic strengthening of inhibitory synapses is mediated by the accumulation of GABA(A) receptors. J Neurosci 31:17701-12
Rajasekaran, Karthik; Joshi, Suchitra; Sun, Chengsan et al. (2010) Receptors with low affinity for neurosteroids and GABA contribute to tonic inhibition of granule cells in epileptic animals. Neurobiol Dis 40:490-501
Lawrence, Courtney; Martin, Brandon Scott; Sun, Chengsan et al. (2010) Endogenous neurosteroid synthesis modulates seizure frequency. Ann Neurol 67:689-93
Chen, Xiangdong; Shu, Shaofang; Schwartz, Lauren C et al. (2010) Homeostatic regulation of synaptic excitability: tonic GABA(A) receptor currents replace I(h) in cortical pyramidal neurons of HCN1 knock-out mice. J Neurosci 30:2611-22

Showing the most recent 10 out of 25 publications