A Reverse Translation Mouse Model for Schizophrenic Psychosis: Contribution of Hippocampal Subfield Pathology
Southcott, Sarah Ann
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Schizophrenia is a serious and lifelong psychotic illness that affects all aspects of cognitive and affective function and whose etiology and brain mechanisms remain elusive. Schizophrenia affects not only those who express the condition, but also their family members, friends, and society as a whole. There is a worldwide prevalence of 1%, and the illness in 2012 alone, cost the USA an estimated $62.7 billion in medical care cost and lost wages. Schizophrenia is an extremely complex disease with a heterogeneous mixture of symptoms, including cognitive dysfunction, mood dysfunction, negative symptoms, and the defining symptom set, positive psychotic symptoms. The antipsychotic effects of dopamine receptor antagonists led people to hypothesize that schizophrenia is a disorder of dopamine hyperfunction, but considerable research has generated no strong evidence to support such a simple mechanistic hypothesis. Most recently, the glutamate system has become an etiologic focus in schizophrenia research and its research is proving more promising. We have studied the molecular basis of psychosis in human post mortem hippocampus in schizophrenia, and its related proteins important for learning and memory, especially the n-methyl-d-aspartate (NMDA) glutamate receptor system. Based on our findings we have developed a testable hypothesis of psychosis, formulated as a learning and memory disorder. In order to fully test this hypothesis we first needed to create a dynamic animal model based on our tissue findings that could be manipulated and probed. We found that knocking out the obligate subunit (GluN1) of the NMDA receptor selectively in the dentate gyrus paradoxically led to an increase in neuronal activity in the CA3 and several behavioral changes parallel to those we observe in schizophrenia. Furthermore we combined a pharmacological risk factor (phencyclidine) and a genetic risk factor (DISC1) with the knockout mouse that we believed would have the highest probability of interacting in a manner reminiscent of schizophrenia. These particular combinations did not exacerbate the symptoms of the dentate gyrus-specific GluN1 knockout mouse. Now we plan to use this dynamic mouse preparation to study the mechanisms whereby the reduction in GluN1 protein in dentate gyrus sensitizes and stimulates neuronal activity downstream within the hippocampus to better understand psychosis processes.