Theses Doctoral

Aberrant assembly and function of a hippocampal circuit in a genetic mouse model of schizophrenia

McKellar, Heather Marie

Schizophrenia is highly heritable yet very few genetic risk variants have been unequivocally linked to the disease. Disrupted in Schizophrenia 1 (DISC1), was first discovered in a family with a balanced translocation t (1; 11) (q42; q14) and a history of psychiatric disease that segregates with the translocation. We created the Disc1Tm1Kara mice, an etiologically valid genetic mouse model which mimics the effect of the human translocation. Disc1 is highly expressed in the dentate gyrus of the hippocampus of adult mice, a region that is important for learning and memory. Disc1Tm1Kara mutant mice have specific deficits in spatial working memory, a process that requires the interconnectivity of the hippocampus and prefrontal cortex. Electrophysiological recordings in the dentate gyrus region find deficits in short term plasticity and decreases in the excitability of mature granule cells. Moreover, the dentate gyrus is one of two regions in the brain where adult neurogenesis occurs and this process is believed to be important for encoding new memories. Disc1Tm1Kara mutant mice have a 20% reduction in neurogenesis and alterations in the architecture of the dendrites and mossy fiber axonal projections of the granule cells in the dentate gyrus of both early postnatal and adult mice. Biochemical evidence suggests a link between Disc1 and the phosphodiesterase, PDE4B, which is important for the degradation of cAMP. Disc1Tm1Kara mutant mice also have decreases in levels of many isoforms of PDE4 as well as increases in cAMP and its downstream target pCREB. Finally, Nrp1 and Sema3A, guidance cues that are regulated by cAMP, are altered in the Disc1Tm1Kara mutant mice. Overall, this mouse is a valuable model of a known genetic variant of schizophrenia susceptibility and adds to our understanding of the pathology of the disease. Abnormalities of the structure, organization, and synaptic plasticity of granule cells of the dentate gyrus are likely caused by the changes in intracellular signaling and contribute to the alterations in connectivity within the trisynaptic circuit and the behavioral deficits of the Disc1Tm1Kara mutant mouse.



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More About This Work

Academic Units
Cellular, Molecular, Structural, and Genetic Studies
Thesis Advisors
Gogos, Joseph A.
Ph.D., Columbia University
Published Here
June 6, 2012