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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH084194-03
Application #
7822826
Study Section
Special Emphasis Panel (ZNS1-SRB-P (44))
Program Officer
Gilotty, Lisa
Project Start
2008-07-01
Project End
2012-04-30
Budget Start
2010-05-01
Budget End
2011-04-30
Support Year
3
Fiscal Year
2010
Total Cost
$303,250
Indirect Cost
Name
University of Mississippi Medical Center
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
928824473
City
Jackson
State
MS
Country
United States
Zip Code
39216
Zhou, Xiaoming; Lu, Jordan Y-F; Darling, Ryan D et al. (2015) Behavioral training reverses global cortical network dysfunction induced by perinatal antidepressant exposure. Proc Natl Acad Sci U S A 112:2233-8
Fan, Lir-Wan; Bhatt, Abhay; Tien, Lu-Tai et al. (2015) Exposure to serotonin adversely affects oligodendrocyte development and myelination in vitro. J Neurochem 133:532-43
Khatri, Nidhi; Simpson, Kimberly L; Lin, Rick C S et al. (2014) Lasting neurobehavioral abnormalities in rats after neonatal activation of serotonin 1A and 1B receptors: possible mechanisms for serotonin dysfunction in autistic spectrum disorders. Psychopharmacology (Berl) 231:1191-200
Alzghoul, Loai; Bortolato, Marco; Delis, Foteini et al. (2012) Altered cerebellar organization and function in monoamine oxidase A hypomorphic mice. Neuropharmacology 63:1208-17
Harris, Sharonda S; Maciag, Dorota; Simpson, Kimberly L et al. (2012) Dose-dependent effects of neonatal SSRI exposure on adult behavior in the rat. Brain Res 1429:52-60
Lu, Yuefeng; Simpson, Kimberly L; Weaver, Kristin J et al. (2012) Differential distribution patterns from medial prefrontal cortex and dorsal raphe to the locus coeruleus in rats. Anat Rec (Hoboken) 295:1192-201
Darling, Ryan D; Alzghoul, Loai; Zhang, Junlin et al. (2011) Perinatal citalopram exposure selectively increases locus ceruleus circuit function in male rats. J Neurosci 31:16709-15
Zhang, Junlin; Darling, Ryan D; Paul, Ian A et al. (2011) Altered expression of tyrosine hydroxylase in the locus coeruleus noradrenergic system in citalopram neonatally exposed rats and monoamine oxidase a knock out mice. Anat Rec (Hoboken) 294:1685-97
Rodriguez-Porcel, Federico; Green, Donald; Khatri, Nidhi et al. (2011) Neonatal exposure of rats to antidepressants affects behavioral reactions to novelty and social interactions in a manner analogous to autistic spectrum disorders. Anat Rec (Hoboken) 294:1726-35
Simpson, Kimberly L; Weaver, Kristin J; de Villers-Sidani, Etienne et al. (2011) Perinatal antidepressant exposure alters cortical network function in rodents. Proc Natl Acad Sci U S A 108:18465-70

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