Investigation of the effects of increased neurosteroid exposure on the maturing cerebral cortex highlights the importance of the downstream effects of stress on cortical development. In particular, nonspecific stress is the most consistent factor recognized in the development of a schizophrenia-vulnerable phenotype. Indeed, monozygotic twin studies show low concordance rates for schizophrenia, thus other factors must play a critical role, including maternal infection, toxic exposure, or traumatic insult during gestation or early childhood, all of which are associated with or contribute to prenatal stress. The GABA-modulatory neurosteroid allopregnanolone is present in the cortex throughout gestation and levels of allopregnanolone in cortex increase in response to stress. The overarching goal of this project, """"""""Developmental Effects of Neurosteroid Exposure and the Etiology of Schizophrenia,"""""""" is to investigate GABAergic neurosteroids as a candidate mechanism in neural development and the etiology of schizophrenia. The investigator will characterize the effects of exogenous neurosteroid exposure on the migration of neurons in the prefrontal cortex and the functional consequences of this exposure at maturity in rats. The temporal and spatial characteristics of the development of the PFC of the rodent make it uniquely vulnerable to the influence of GABA signaling and changes in cortical neurosteroid levels. Based on the data from her previous research, she hypothesizes that neurosteroids play a modulatory role in the regulation of cortical ontogeny and connectivity, and that dysfunction in the neurosteroid modulation of GABAergic neurotransmission alters the developing nervous system and leads to developmental deficits resulting in a schizophrenia-vulnerable phenotype. To test this hypothesis, the investigator will, in Specific Aim 1, investigate the effects of neonatal neurosteroid exposure on cortical neuron migration;and in Specific Aim 2, investigate the neurochemical identity of cell populations mislocalized after neonatal allopregnanolone exposure.
Schizophrenia is a devastating and debilitating mental illness that places an immense burden on the community, especially in underserved populations where treatment access and outcome often fall short of expected norms. Understanding the nongenetic factors that play a role in the etiology of the disorder across development will lead to preventative interventions that may reduce the incidence of schizophrenia or lessen its impact on the community at large.
