Department or Program

Neuroscience

Abstract

Pitt-Hopkins Syndrome is a rare Autism spectrum disorder presenting with severe intellectual disability, which results from haploinsufficiency of Tcf4. Presently, there is no treatment for Pitt-Hopkins, and currently no permanent means by which cognition may be enhanced in a living organism. While it remains elusive how long-term memories are formed and maintained, an emerging literature suggests that one of the underlying factors are epigenetic modifications to the genome, such as DNA methylation. To understand specific molecular aberrations which may underpin certain aspects of cognitive dysfunction in Pitt-Hopkins Syndrome, we first identified dysregulated gene expression in left versus right hippocampal tissue in Tcf4 (+/-) mice compared to wild type mice. Next, we constitutively knocked down Tet1 in Tcf4 (+/-) and wild type mice and Tet2 acutely within the central nervous system of wild type mice to test the hypothesis that the TET proteins are responsible for the demethylation of plasticity-regulated genes. Last, we examined the effect of Tet1 and Tet2 knockdown on learning and memory in Tcf4 (+/-) and wild type mice, respectively. We found that there were substantially more dysregulated genes in the left hippocampus as compared to the right hippocampus, leading to dysfunction in molecular pathways specific to the left hippocampus. We also observed that while Tet1 knockdown did not enhance learning and memory compared to wild type, Tet2 knockdown in wild type mice enhanced spatial memory. Last, the Tcf4/Tet1 double knockout mice exhibited significantly enhanced memory as compared to Tcf4 (+/-) mice.

Level of Access

Restricted: Embargoed [Bates Community After Expiration]

First Advisor

Kennedy, Andrew

Date of Graduation

5-2017

Degree Name

Bachelor of Science

Number of Pages

164

Components of Thesis

1 pdf file

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Embargoed

Available to Bates Community via local IP address or Bates login on Saturday, May 01, 2027.

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