Degree

Doctor of Philosophy (PhD)

Department

Comparative Biomedical Sciences

Document Type

Dissertation

Abstract

Schizophrenia is a neurodevelopmental disorder characterized by positive, negative and cognitive impairment symptoms. The disease has a high heritability, but concordance in monozygotic twins is not 100 percent. Among the bevy of causal factors, gene-environmental interactions are considered critical to its pathogenesis. Neurobiologically, imbalanced excitatory and inhibitory interactions in the cerebral cortex are a constant finding in psychiatric disorders such as schizophrenia. These are mediated by inhibitory interneurons that modulate excitatory output from pyramidal cells. Parvalbumin (PV) positive interneurons (basket and chandelier cells) form one of the largest populations of this modulatory inhibitory circuitry in the cortex. These cells are fast-spiking, highly metabolically active, and surrounded by perineuronal nets (PNNs). PNNs are extracellular matrix structures known to act as a cation sink and protect PV interneurons from oxidative stress. These interneurons and associated PNNs vary in number and distribution across ages and brain regions in an individual.

Here, we used a DISC1 (Disrupted in. Schizophrenia) gene mutation mouse model to study schizophrenia. DISC1 is a scaffolding protein, with no known enzymatic activity. This protein interacts with over 200 proteins/molecular partners affecting neuronal proliferation, migration and energy dynamics. DISC1 impacts the number of PNNs and PVs in brain, but with an unknown developmental and aging time course. Moreover, the impact of DISC1 mutation on various signaling pathways is largely unknown. Using this mouse model, behavioral phenotypic differences were characterized when environmental stresses were imposed, i.e. maternal separation of pups and administration of N-methyl-D-aspartate receptor (NMDAR) antagonist (ketamine injections). To understand the molecular impacts due to this mutation, we examined the IGF-1R pathway and related kinases. Cognitive and long-term potentiation (LTP) impairment being the constant finding in schizophrenia symptoms, we noted the impact of DISC1 mutation on calcium activated small ion channels, i.e. SK2 channels, and associated activation of calcium/calmodulin binding protein kinase II-α (CamKII-α) and its impact on NMDAR in LTP.

Date

1-17-2020

Committee Chair

Lee, Charles

Available for download on Saturday, January 09, 2027

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