Date of Award

2014

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Cell & Molecular Biology

First Advisor

Ted Abel

Abstract

Neurodevelopmental and neuropsychiatric disorders are a significant and expanding global health crisis. Many individuals affected by these disorders have social and cognitive symptoms represent significant sources of ongoing disability that are refractory to available treatment options. The search for cures and therapies for disorders fundamentally requires an understanding of the core neuropathology and insight into the underlying molecular mechanisms at work. In this dissertation, I describe experiments that we performed to explore molecular and genetic mechanisms underlying memory impairment and enhancement in mice. Synaptic structural proteins form a critical and adjustable framework that supports recruitment of neurotransmitter receptors and facilitates signal transduction. In Chapter 2, we explored a role for the autism-related gene Protocadherin 10 (Pcdh10) as a key regulator of dendritic spine morphology and synapse elimination. We found that mice with reduced PCDH10 have deficits in amygdala function, including impairments in conditioned fear, social interactions and gamma synchrony, as well as increased density of immature filopodia-type spines. In the second part of this dissertation, we showed that the co-repressor SIN3A is a negative regulator of memory formation. In Chapter 3, we demonstrated that reducing levels of SIN3A enhances in long-term memory and hippocampal synaptic plasticity, and increases expression of Homer1, a gene encoding a post-synaptic density protein that regulates signaling through metabotropic glutamate receptors. In Chapter 4, we identified contextual fear deficits in transgenic mice expressing Cre recombinase in forebrain neurons. These results expand our understanding of molecular mechanisms of memory formation, and identify new therapeutic targets for improving cognitive function.

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