Autism spectrum disorder or Autism (ASD) is among one of the most devastating neurodevelopmental disorders in the United States. The most current epidemiological data have suggested that this disorder may affect as many as 1 in 150 children. Unfortunately, the scientific community is at a loss to explain the increased prevalence of this disorder among the American population in recent years. Based on limited neuropathological and fMRI studies, investigators have been able to determine that the most consistent anatomical abnormality in ASD relates to a reduction in the size of the corpus callosum (a major fiber bundle in the brain which connects the two cerebral hemispheres). In the absence of a suitable animal model for ASD, we have learned that serotonin (5HT) plays a critical role during early brain development, and that 5HT synthesis is altered in autistic individuals at early ages. Importantly, our recently published data and other lines of evidence have revealed that brief perinatal exposure of rat pups to the selective serotonin reuptake inhibitor (SSRI), citalopram, can alter uptake of fluorescent tracer from one cerebral hemisphere to another and lead to malformation of myelin sheaths around callosal axons. Hence, our central hypothesis is that abnormal regulation of 5HT during early brain development compromises oligodendrocyte function and interferes with the establishment of normal interhemispheric connections. To address our hypothesis, multi-disciplinary approaches which include anatomy, immunohistochemistry, physiology, pharmacology, behavior, as well as cell culture will be simultaneously conducted from a group of world leading scientists at three different institutions. These studies are designed to define the possible role of serotonin dysregulation in the genesis of autism and related pervasive developmental disorders. We believe that our proposed exploratory studies hold great promise in identifying a future animal model for ASD, and hold the key to linking serotonin dysfunction during early brain development to increased rates of maternal SSRI usage during pregnancy and nursing. Our findings should 1) shape public policy regarding the identification and rehabilitation of individuals with ASD, and 2) help to establish antidepressant treatment guidelines for new and expectant mothers. Neurodevelopmental disorders have a tremendous impact on our society. At present, autism spectrum disorder (ASD) is among one of the most devastating diseases affecting children in terms of prevalence, morbidity, disruption to family life, and cost to the public. According to the most recent epidemiological data, ~ 1 child in 150 suffers from ASD. However, the etiology of this disorder is largely unknown. Interestingly, ASD is characterized by a reduction in the size of the corpus callosum;a sign of underconnectivity between the two cortical hemispheres. Based on our preliminary data and other lines of evidence, we propose that dysfunction of the raphe serotonin (5HT) system during early development may be one of the most important factors contributing to ASD. The most challenging and clinical relevant aspects of this proposal is our attempt to link recent drastic increase of ASD to the increased number of mothers taking antidepressant drugs, namely selective serotonin reuptake inhibitors (SSRIs), during pregnancy and nursing. Hence, our central hypothesis is that abnormal regulation of 5HT during early brain development interferes with myelin formation and the establishment of normal inter-hemispheric connections. The proposed experiments are designed to address this hypothesis by studying anatomical, neurochemical, physiological, and behavioral effects of perinatal citalopram (the most selective SSRI) exposure on rats aged to postnatal days 22 and >90.
Neurodevelopmental disorders have a tremendous impact on our society. At present, autism spectrum disorder (ASD) is among one of the most devastating diseases affecting children in terms of prevalence, morbidity, disruption to family life, and cost to the public. According to the most recent epidemiological data, ~ 1 child in 150 suffers from ASD. However, the etiology of this disorder is largely unknown. Interestingly, ASD is characterized by a reduction in the size of the corpus callosum;a sign of underconnectivity between the two cortical hemispheres. Based on our preliminary data and other lines of evidence, we propose that dysfunction of the raphe serotonin (5HT) system during early development may be one of the most important factors contributing to ASD. The most challenging and clinical relevant aspects of this proposal is our attempt to link recent drastic increase of ASD to the increased number of mothers taking antidepressant drugs, namely selective serotonin reuptake inhibitors (SSRIs), during pregnancy and nursing. Hence, our central hypothesis is that abnormal regulation of 5HT during early brain development interferes with myelin formation and the establishment of normal inter-hemispheric connections. The proposed experiments are designed to address this hypothesis by studying anatomical, neurochemical, physiological, and behavioral effects of perinatal citalopram (the most selective SSRI) exposure on rats aged to postnatal days 22 and >90.
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