Date of Award

2018

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Neuroscience

First Advisor

Robert G. Kalb

Abstract

The goal of this dissertation is to further understand the genetic architecture of neuropsychiatric disorders, such as autism spectrum disorder (ASD) and schizophrenia (SCZ). We attempt to understand the functional significance of the gene synapse associated protein of 97KDa (SAP97) and identify a novel role for SAP97 in the etiology of neuropsychiatric disorders.

SAP97 belongs to a family of scaffolding proteins, the membrane-associated guanylate kinases (MAGUKs), that are highly enriched in the postsynaptic density of synapses and play an important role in organizing protein complexes necessary for synaptic development and plasticity. Large-scale genetic studies have implicated MAGUKs in neuropsychiatric disorders such as intellectual disability, ASD, and SCZ, but knock-out mice have been impossible to study because the Sap97 null mice die soon after birth due to a craniofacial defect. In Chapter 2, we studied the transcriptomic and behavioral consequences of a viable, brain-specific conditional knockout of Sap97 (SAP97-cKO). RNA sequencing (RNAseq) from hippocampi from control and SAP97-cKO male animals identified 67 differentially expressed transcripts, which were specifically enriched for SCZ-related genes. Subjecting SAP97-cKO mice to a battery of behavioral tests revealed a subtle anxiety-like phenotype present in both male and female SAP97-cKO animals, as well as a mild male-specific cognitive deficit and female-specific motor learning deficit. Collectively, this work suggests that loss of Sap97 alters behavior, and may contribute to some of the endophenotypes present in SCZ. In Chapter 3, we discuss how the SAP97-cKO mouse may serve as a novel model system for interrogating aspects of the cellular and molecular defects underlying SCZ and other related neuropsychiatric disorders.

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