This competitive revision application extends from MH051699, """"""""Receptor-mediated lysophosphatidic acid (LPA) signaling in cortical development"""""""" that is focused on LPA signaling as a novel, lipid influence on cerebral cortical development. It is responsive to the NIMH revision application targeted topic """"""""Understanding Postnatal Brain Development,"""""""" since the parent proposal was limited to prenatal studies. We have found that exposure to intracerebral LPA in utero can produce obvious postnatal behavioral sequelae that are reminiscent of neuropsychiatric dysfunction in children and adolescents. This observation is remarkable because of the unexplained epidemiological linkages, validated in numerous independent studies, which report a statistically significant increase in the incidence of mental health related diseases - that include autism and schizophrenia - in patients who were subject to prenatal fetal or maternal bleeding as well as fetal viral infection. A significant bi- product of bleeding and viral infection is the production of LPA that could therefore provide a molecular link to explain in part this epidemiological observation. In the revision application, I will test the hypothesis that stereotyped behavioral dysfunction can be produced by intracerebral LPA exposure during fetal life that is mediated by LPA receptors through 2 specific aims.
Aim 1 will produce live cohorts of animals exposed in utero to intracerebral LPA and test them behaviorally.
Aim 2 will determine the postnatal effects of genetic and pharmacological interruption of LPA signaling. Pursuance of these aims will provide new insights on the actions of signaling lipids on brain development, function, and animal behavior. It may also lead to rational approaches, based on LPA receptor modulation, for preventing or treating mental health disorders that have developmental etiologies.
This proposal has relevance to human health through exploring a novel mechanism that could in part account for mental health diseases like autism or schizophrenia. Over the next 19 months, the proposal will test the hypothesis that stereotyped behavioral dysfunction can be produced by intracerebral LPA exposure during fetal life that is mediated by LPA receptors. It will do so via two specific aims.
Aim 1 will expose animals in utero to intracerebral LPA and test live cohorts behaviorally, via 3 experiments. Experiment 1 will produce LPA-injected cohorts of female survivors. Experiment 2 will use a battery of behavioral tests to screen for defects longitudinally at 3 ages: adolescence (35 days), young adulthood (90 days), and in middle age (270 days). Experiment 3 will histologically assess sample animals associated with behavioral alterations at each age. These studies will be complemented by assessing LPA receptor mechanisms in Aim 2 that will determine the postnatal effects of genetic and pharmacological interruption of LPA signaling. Experiment 1 will repeat Experiments 1 &2, Aim 1, using mice null for the receptor LPA1 and test these animals in a limited behavioral assessment based upon observed defects in Aim 1. Experiment 2 will repeat Experiment 1, Aim 2 on wildtype animals pretreated with an LPA1 receptor antagonist and again assess behavior. Experiment 3 will assess samples from Experiments 1 &2 histologically. Pursuance of these aims will provide new insights on the actions of signaling lipids on brain development, function, and animal behavior. It may also lead to rational approaches, based on LPA receptor modulation, for preventing or treating mental health disorders with developmental etiologies.
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