Gut dysbiosis and 5-HT2A dysregulation in a preclinical schizophrenia model

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Project Summary/Abstract The pathophysiology of schizophrenia is complex and, despite significant advances in understanding the development of this disorder, available treatments will not produce a response in a significant subset of patients. This fact, combined with the significant morbidity associated with currently available antipsychotics, highlights a need for novel approaches to understanding schizophrenia pathophysiology and developing new treatments. The gut microbiome has emerged as a contributor to neuropsychiatric disorders in humans and behavioral alterations in rodents, but has not been extensively investigated within the context of schizophrenia. Interestingly, the microbiome has been demonstrated to affect expression of the serotonin 5-HT2A receptor, which has been well implicated within human schizophrenia as well as animal models of the disorder. Our group has demonstrated that both antipsychotic-free postmortem samples from human schizophrenia patients and offspring mice within a maternal immune activation model of schizophrenia display increased density of the receptor in the prefrontal cortex. Mice within this model also display increased rates of the psychosis-like, 5-HT2A receptor-dependent head twitch response. Other groups have demonstrated association of the receptor with schizophrenia-related phenotypes such as altered function of cortical pyramidal neurons and sensorimotor gating deficits. We therefore propose to investigate the role of the gut microbiome in the development of 5-HT2A receptor alterations and subsequent schizophrenia-like phenotypes in an influenza virus-induced maternal immune activation model of schizophrenia in mice. Transgenic mice, molecular biology techniques, rodent behavioral assays, and microscopy will be used to accomplish these goals. Our results have the potential to further understanding of the pathophysiology of schizophrenia and implication of the gut microbiome in schizophrenia would allow for investigation into new targets for therapy and prevention. The training plan proposes to develop the applicant’s scientific and clinical abilities via introduction to experimental techniques relevant to molecular biology, mouse behavior, dendritic spine analysis, and manipulation of the gut microbiome; development of essential skills such as scientific communication, statistical analysis, hypothesis generation and testing, and ethics; enhancement of clinical skills during medical school clerkships; and addition of scientific knowledge through venues such as seminars and journal clubs. The environment in which the proposed research will take place possesses the equipment necessary to conduct the work, a wealth of core facilities including the Microscopy and Transgenic Mouse cores, and faculty with expertise in a breadth of areas including psychiatric genetics, microscopy, and neuroscience.