Over the past decade, a combination of genetic, biological and imaging approaches have identified Disrupted-in-Schizophrenia-1 (DISC1) as a strong susceptibility gene for psychiatric illnesses including schizophrenia, bipolar disorder and major depression. DISC1 regulates various neurodevelopmental processes including neurogenesis, neuronal migration, neurite outgrowth, spine development and neurotransmitter signaling. Human post-mortem brain studies in schizophrenia have revealed some consistent neuropathological findings such as abnormal neuron morphology, reduced spine density, aberrant cytoarchitecture and interneuron deficits in the dorsolateral prefrontal cortex and hippocampus. However, the etiology and development of these histological abnormalities remain unclear.
Therefore, we investigated brain histology of two independently-derived Disc1 mutant mice with point mutations (Disc1-Q31L and -L100P). Both mutants displayed reductions in cortical neuron density, decreased neurogenesis and altered cortical neuron distribution when compared to wild-type controls. Frontal cortical pyramidal neurons had shorter dendrites and reduced dendritic surface area. Spine density was also reduced on apical dendrites of both frontal cortical and hippocampal pyramidal neurons. In addition, we observed a pronounced defect in tangential migration of interneurons in the embryonic brains of Disc1-L100P mutants when compared to wild-type mice. Adult Disc1-L100P mutants also have selective alterations of calbindin- and parvalbumin-expressing interneurons in the cortex and hippocampus, decreased glutamate decarboxylase 67/parvalbumin co-localization and mis-positioned interneurons across the neocortex.
Finally, we investigated the effects of GSK3α inactivation on frontal cortical neuron morphology in Disc1-L100P mutants. Disc1-L100P, GSK3α -/- and 100P/100P;GSK3α double mutants all exhibited significant reductions in dendritic length and surface area while spine density was significantly reduced only in Disc1-L100P and 100P/100P;GSK3α +/- mutants when compared to wild-type mice. Interestingly, spine density was rescued in 100P/100P;GSK3α -/- double mutants and comparable to wild-type mice. Overall, these findings are consistent with the anomalies seen in post-mortem schizophrenia studies and other Disc1 mutant mouse models, providing further evidence that DISC1 participates in neurodevelopment. GSK3 is only one of many pathways modulated by DISC1, so more research is required to fully understand how the network of DISC1-interacting proteins is involved in the pathophysiology of psychiatric disorders. Better understanding of these mechanisms could lead to the development of new treatments.
| Identifer | oai:union.ndltd.org:TORONTO/oai:tspace.library.utoronto.ca:1807/35876 |
| Date | 08 August 2013 |
| Creators | Lee, Frankie Hang Fung |
| Contributors | Wong, Albert Hung Choy |
| Source Sets | University of Toronto |
| Language | en_ca |
| Detected Language | English |
| Type | Thesis |
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