Estrogen promotes seizure activity both in women with epilepsy and in animal models of epilepsy, but the cellular events that underlie estrogen promotion of seizures are not known. It is known that estrogen induces changes in the structure and function of excitatory synapses in the hippocampus that are likely to increase seizure susceptibility. Estrogen increases the density and number of dendritic spines (sites of excitatory synaptic connections) and spine synapses on hippocampal neurons, increases hippocampal neurons' sensitivity to excitatory synaptic input, and increases the divergence of excitatory synaptic input from individual presynaptic cells to multiple postsynaptic cells; these changes in synaptic connectivity are associated with greater susceptibility to hippocampus-dependent behavioral seizures. Knowledge of the mechanism(s) by which these estrogen-induced changes in hippocampal synapses occur is critical to understanding cellular processes leading to synaptic rearrangements that increase seizure susceptibility. ? ? We developed a novel system for organotypic slice culture of adult rat hippocampus that models changes in hippocampal circuitry induced by estrogen in vivo. This new in vitro system allows analyses of estrogen regulation of hippocampal circuitry using approaches that are not possible with in vivo experiments. In the proposed studies, we will perform both in vivo manipulations in adult female rats and in vitro manipulations in adult slice cultures to answer three key questions about the mechanisms of estrogen's effects on hippocampal synaptic connectivity: 1) What is the role of subcortical structures, particularly cholinergic neurons in basal forebrain? 2) What type(s) of estrogen receptors are involved? 3) What is the role of disinhibition? ? ? The proposed studies will integrate anatomical and electrophysiological measures of estrogen's effects on excitatory and inhibitory synaptic interactions in the hippocampus with behavioral analyses of seizure susceptibility. As such, these studies will reveal new information about the cellular mechanisms by which estrogen-induced changes in synaptic connectivity occur and will rigorously test the association of structural and functional changes in hippocampal synaptic connectivity with seizure susceptibility. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
2R01NS037324-06
Application #
6580629
Study Section
Special Emphasis Panel (ZRG1-BDCN-2 (01))
Program Officer
Jacobs, Margaret
Project Start
1998-09-30
Project End
2007-11-30
Budget Start
2002-12-01
Budget End
2003-11-30
Support Year
6
Fiscal Year
2003
Total Cost
$282,863
Indirect Cost
Name
Northwestern University at Chicago
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
160079455
City
Evanston
State
IL
Country
United States
Zip Code
60201
Sato, Satoru M; Woolley, Catherine S (2016) Acute inhibition of neurosteroid estrogen synthesis suppresses status epilepticus in an animal model. Elife 5:
Shansky, Rebecca M; Woolley, Catherine S (2016) Considering Sex as a Biological Variable Will Be Valuable for Neuroscience Research. J Neurosci 36:11817-11822
Tabatadze, Nino; Woolley, Catherine (2016) Measurement of Inositol Triphosphate Levels from Rat Hippocampal Slices. Bio Protoc 6:
Tabatadze, Nino; Huang, Guangzhe; May, Renee M et al. (2015) Sex Differences in Molecular Signaling at Inhibitory Synapses in the Hippocampus. J Neurosci 35:11252-65
Tabatadze, Nino; Sato, Satoru M; Woolley, Catherine S (2014) Quantitative analysis of long-form aromatase mRNA in the male and female rat brain. PLoS One 9:e100628
May, Renee M; Tabatadze, Nino; Czech, Mary M et al. (2014) Estradiol regulates large dense core vesicles in the hippocampus of adult female rats. Brain Struct Funct 219:1947-54
Tabatadze, Nino; Smejkalova, Tereza; Woolley, Catherine S (2013) Distribution and posttranslational modification of synaptic ER* in the adult female rat hippocampus. Endocrinology 154:819-30
Huang, Guang Zhe; Woolley, Catherine S (2012) Estradiol acutely suppresses inhibition in the hippocampus through a sex-specific endocannabinoid and mGluR-dependent mechanism. Neuron 74:801-8
Snyder, Melissa A; Cooke, Bradley M; Woolley, Catherine S (2011) Estradiol potentiation of NR2B-dependent EPSCs is not due to changes in NR2B protein expression or phosphorylation. Hippocampus 21:398-408
Smejkalova, Tereza; Woolley, Catherine S (2010) Estradiol acutely potentiates hippocampal excitatory synaptic transmission through a presynaptic mechanism. J Neurosci 30:16137-48

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