Estrogen promotes seizure activity both in women with epilepsy and in animal models of epilepsy, but thecellular events that underlie estrogen promotion of seizures are not known. It is known that estrogen induceschanges in the structure and function of excitatory synapses in the hippocampus that are likely to increaseseizure susceptibility. Estrogen increases the density and number of dendritic spines (sites of excitatorysynaptic connections) and spine synapses on hippocampal neurons, increases hippocampal neurons'sensitivity to excitatory synaptic input, and increases the divergence of excitatory synaptic input fromindividual presynaptic cells to multiple postsynaptic cells; these changes in synaptic connectivity areassociated with greater susceptibility to hippocampus-dependent behavioral seizures. Knowledge of themechanism(s) by which these estrogen-induced changes in hippocampal synapses occur is critical tounderstanding 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 changesin hippocampal circuitry induced by estrogen in vivo. This new in vitro system allows analyses of estrogenregulation of hippocampal circuitry using approaches that are not possible with in vivo experiments. In theproposed studies, we will perform both in vivo manipulations in adult female rats and in vitro manipulations inadult slice cultures to answer three key questions about the mechanisms of estrogen's effects onhippocampal synaptic connectivity: 1) What is the role of subcortical structures, particularly cholinergicneurons in basal forebrain? 2) What type(s) of estrogen receptors are involved? 3) What is the role ofdisinhibition? The proposed studies will integrate anatomical and electrophysiological measures of estrogen's effects onexcitatory and inhibitory synaptic interactions in the hippocampus with behavioral analyses of seizuresusceptibility. As such, these studies will reveal new information about the cellular mechanisms by whichestrogen-induced changes in synaptic connectivity occur and will rigorously test the association of structuraland functional changes in hippocampal synaptic connectivity with seizure susceptibility.
|Effective start/end date||12/1/02 → 11/30/07|
- National Institute of Neurological Disorders and Stroke (2 R01 NS037324-06)