UC San Diego

Serious mental illnesses are debilitating and costly, and the development of effective treatments is imperative. Unfortunately, their heterogeneous and overlapping etiologies and symptomatologies present major obstacles to our understanding of these disorders. Carefully designed animal models and test paradigms with precise cross-species valid outcomes enable us to investigate the mutations, network disruptions, and environmental challenges that contribute to the development of neuropsychiatric symptoms and may be targeted for treatment. This dissertation presents two mouse models developed to study candidate risk genes associated with neuropsychiatric illnesses, including major depression, bipolar disorder, and schizophrenia. The studies presented herein provide insight into the development and potential treatments for these disorders.

Studies of humanized DISC1-Boymaw mice focus on the effects of a rare translocation associated with psychiatric illnesses in a large Scottish family. Our studies suggest that inhibition of protein synthesis and mitochondrial dysfunction resulting from the fusion of the DISC1 and Boymaw genes may contribute to the pathogenesis of illnesses in this family. The DISC1-Boymaw mice exhibit hypersensitivity to ketamine, a phenotype also observed in patients and in the other rare variant model presented here, the Sp4 hypomorphic (Hyp) mice, which have reduced expression of the transcription factor Sp4. Our investigation of Sp4 Hyp mice suggests that hypersensitivity to ketamine is mediated by inhibitory GABAergic neurons and not excitatory forebrain neurons.

Dysfunction of GABAergic neurons may be associated with cognitive and motivational deficits observed in the Sp4 Hyp mice and in patients. The cognitive deficits associated with psychiatric illnesses are predictive of vocational and social outcomes and should be prioritized in the development of treatments. Our studies suggest that a glycine type-1 transporter (GlyT-1) inhibitor may remediate attention deficits—but not impairments to motivation nor reward learning—in these mice and potentially in patients. It is the author’s hope that the findings presented in this dissertation and follow-up studies will contribute to the understanding and development of treatments for neuropsychiatric disorders.