Date of Award

8-11-2008

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Biology

First Advisor

Patrick A. Carr

Abstract

Catecholaminergic input, acting through adrenergic receptors (AR), serves an important role in regulating the activity of the hippocampus; however, the synaptic elements whereby the abundant input mediates its actions remains obscure. Immunohistochemical and molecular biological techniques and a variety of experimental animal models, were used to examine the adrenergic receptor profiles displayed by distinct populations of neurons (interneurons and principal cells) or glial in rodent hippocampus. In the adult rat, immunoreactive puncta for eight of the nine adrenergic receptor subtypes were differentially distributed amongst regional glia, blood vessels, and neurons of the subiculum, hippocampus proper and dentate gyrus. Developmentally, there was a noticeable change in the distribution and abundance of labeling for seven of the adrenergic receptor subunits. Pathological conditions which directly impacted the hippocampus were also found to alter the distribution and abundance of adrenergic receptors in comparison to control animals. Seizure states induced by kainic acid, pentylenetetrazole, and pilocarpine resulted in marked changes in the cellular and subcellular localization of receptor labeling. Results obtained using immunohistochemical methodologies were supported by the implementation of novel lines of transgenic mice. Mice which overexpressed α1B-AR displayed an age-dependent decrease in the number of hippocampal interneurons, contrasting the increase in interneurons identified in mice overexpressing α1A-AR. When induced to epileptiform seizure, animals overexpressing α 1B-AR displayed decreased seizure latency while animals overexpressing α 1A-AR showed an increased defiance to seizure development. Characterization of the morphological organization of adrenergic receptors within the hippocampus of normal adult and developing rats and experimentally epileptogenic rodent models provided insight into the anatomical constructs underlying previously described physiological and pathological responses. These results suggest a distinct pattern of expression for adrenergic receptors in the developing rat hippocampus. Furthermore, these studies illustrate how seizures acutely affect the distribution of not only adrenergic receptor subtypes, but also calcium binding proteins, neuropeptides and cytoskeletal proteins within neurons throughout the hippocampus and suggest that overexpression of α1A or α1B-AR may result in differential responses to pathological insults. Taken together the results communicated here may have implications regarding the development of novel, more efficient strategies for the treatment of epilepsy through the targeting of adrenergic receptors.

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