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Theses Doctoral

Anatomical and Functional Characterization of the Ventral Hippocampus in a Rodent Model of Schizophrenia Neuropathology

Remole, Kelley E.

Schizophrenia is a debilitating, life-long illness with a still-unknown, complex etiology and, currently, no cure. Many studies have implicated the hippocampus and the parahippocampal region as a place of both primary pathology in the disease and as regions correlated to symptom severity. To better understand the pathophysiology of the region and potentially uncover mechanisms of the disease, the appropriate choice of an animal model is essential. The "MAM E17" model of hippocampal pathology shows anatomical, neurophysiological, and behavioral changes relevant to schizophrenia. Because of these wide-ranging disease-relevant changes, we aimed to relate anatomical to neurophysiological phenotypes in this model. We also performed experiments to assess the feasibility and validity of transferring the MAM E17 model to the mouse in order enable future studies of the genetic basis of the vulnerability or resilience to MAM. In adult offspring of rats exposed to to methylazoxymethanol (MAM) at embryonic day 17 (E17), we found changes in regional hippocampal anatomy and subicular pyramidal cell morphology with homology to abnormalities reported in schizophrenia. Specifically, we found a decrease in dendritic spine density in specific regions of the dendrite of ventral subicular neurons. At the neurophysiological level, we observed abnormalities in afferent-evoked synaptic responses in the ventral subiculum. These changes were not however, accompanied by changes in in vivo spontaneous spike activity in subicular neurons . In the mouse, MAM was found to have much less impact on brain development, as observed at the gross morphological level. However, these mice showed an increased sensitivity to some psychostimulants and a weak trend for metabolic abnormalities relevant to schizophrenia. We conclude from the rat studies that prenatal disruption of brain development by MAM at E17 in the rat, a manipulation that leads to a profile of gross anatomical and cognitive deficits relevant to schizophrenia, also leads to "dysconnectivity" between the ventral subiculum and its inputs. While further work is needed to understand this, we speculate that this synaptic dysconnectivity may contribute to the cognitive deficits in this model and, further, may model an aspect of hippocampal pathophysiology in schizophrenia. A better understanding of these circuits could point to new strategies for treating this disease.



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More About This Work

Academic Units
Neurobiology and Behavior
Thesis Advisors
Moore, Holly M.
Ph.D., Columbia University
Published Here
November 1, 2012