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Autism spectrum disorders

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TitleInfo
Title
Autism spectrum disorders
SubTitle
environmental and genetic risk factors alter cortical neurogenesis
Name (type = personal)
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Connacher
NamePart (type = given)
Robert James
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Robert James Connacher
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author
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DiCicco-Bloom
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Emanuel
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Emanuel DiCicco-Bloom
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Advisory Committee
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chair
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Dreyfus
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Cheryl
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Cheryl Dreyfus
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Advisory Committee
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internal member
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Rasin
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Mladen-Roko
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Mladen-Roko Rasin
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Advisory Committee
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internal member
Name (type = personal)
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D'Arcangelo
NamePart (type = given)
Gabriella
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Gabriella D'Arcangelo
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Advisory Committee
Role
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internal member
Name (type = personal)
NamePart (type = family)
Rabson
NamePart (type = given)
Arnold
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Arnold Rabson
Affiliation
Advisory Committee
Role
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outside member
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NamePart
Rutgers University
Role
RoleTerm (authority = RULIB)
degree grantor
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School of Graduate Studies
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school
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Text
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theses
OriginInfo
DateCreated (qualifier = exact)
2017
DateOther (qualifier = exact); (type = degree)
2017-10
CopyrightDate (encoding = w3cdtf); (qualifier = exact)
2017
Place
PlaceTerm (type = code)
xx
Language
LanguageTerm (authority = ISO639-2b); (type = code)
eng
Abstract (type = abstract)
Cortical Neurogenesis is a highly regulated process which requires neural precursor population expansion followed by migration and subsequent differentiation. Early cortical overgrowth has been observed in individuals with autism spectrum disorder (ASD) and may underpin observed cases of macrocephaly seen within ASD subgroups. To define mechanisms by which this process could be altered, studies have identified environmental and genetic ASD risk factors, including Valproic acid (VPA) and the copy number variant 16p11.2 (16P), respectively. Valproic acid is a neurotheraputic medicine intended to treat epilepsy, migraines, and bipolar disorder but poses ASD risk to prenatally exposed fetuses when mothers are taking this drug. Prenatal VPA exposure in rodents studies have replicated behavioral and cellular deficits seen in ASD, including alterations in neurogenesis, but convergence of mechanisms remain undefined. Studies suggest VPA may impact development through Histone Deacetylase (HDAC) inhibition, though this enzymatic inhibition has not been directly confirmed in primary neural cells. The function of HDACs is to epigenetically regulate acetylation sites which can change gene expression. Therefore, I characterized HDAC message and protein in the developing rodent brain, and confirmed that VPA can enzymatically inhibit these proteins. Previously, we found that VPA exposure promotes G1 to S phase transition through rapid increases of G1 cyclins and acetylated Histone H3, suggesting epigenetic regulation of this process. Therefore, I measured mRNA of G1 cyclins after acute VPA exposure, and found upregulation in transcription of these genes, supporting the notion that post-translational modifications of histones may promote proliferation through G1-S phase transition. Additionally, our prior studies found that the increased proliferation resulted in a bigger brain by P21 with more upper layer neurons. Others have also indicated prenatal VPA exposure promotes neurogenesis of upper layer neurons. Therefore with these findings, I characterized the percentage of Pax6 and Tbr2 progenitor cells in S phase, to determine specificity of VPA effect. Interestingly, only the Tbr2 population had more cells in S phase, providing explanation for increased upper layer neurons at P21. Altered neurogenesis is also observed in the copy number variant 16p11.2, a genetic risk factor for ASD. In the 16p11.2 chromosomal deletion, one copy of 27 genes is missing, including MAPK3, which encodes ERK1. This gene is a central component in the ERK signaling pathway, which is important for regulating cellular growth and proliferation. Therefore, I investigated proliferative changes and signaling alterations in Neural Precursor Cells (NPCs) derived from control and 16p11.2 patients iPSCs. I found that 16p11.2 NPCs had increased DNA synthesis under control media but exhibited reduced responses to mitogenic stimulation with FGF, a developmental extracellular factor known to activate the ERK pathway. Further characterization of this pathway under control conditions revealed equivalent if not elevated phosphorylation of ERK1, but approximately 50% less Total ERK1. Additionally, as may be predicted, there were elevations in cyclin D1 and P-S6, suggesting mechanisms by which DNA synthesis is increased in these cells. In aggregate, these studies identify cortical neurogenesis as a common target of risk factors that contribute to neuropsychiatric diseases.
Subject (authority = RUETD)
Topic
Neuroscience
Subject (authority = ETD-LCSH)
Topic
Autism
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Rutgers University Electronic Theses and Dissertations
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ETD_8388
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electronic resource
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Extent
1 online resource (xv, 154 p. : ill.)
Note (type = degree)
Ph.D.
Note (type = bibliography)
Includes bibliographical references
Note (type = statement of responsibility)
by Robert James Connacher
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Title
School of Graduate Studies Electronic Theses and Dissertations
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rucore10001600001
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NjNbRU
Identifier (type = doi)
doi:10.7282/T3WQ06X0
Genre (authority = ExL-Esploro)
ETD doctoral
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The author owns the copyright to this work.
RightsHolder (type = personal)
Name
FamilyName
Connacher
GivenName
Robert
MiddleName
James
Role
Copyright Holder
RightsEvent
Type
Permission or license
DateTime (encoding = w3cdtf); (qualifier = exact); (point = start)
2017-09-23 01:05:29
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Name
Robert Connacher
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Affiliation
Rutgers University. School of Graduate Studies
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Author Agreement License
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I hereby grant to the Rutgers University Libraries and to my school the non-exclusive right to archive, reproduce and distribute my thesis or dissertation, in whole or in part, and/or my abstract, in whole or in part, in and from an electronic format, subject to the release date subsequently stipulated in this submittal form and approved by my school. I represent and stipulate that the thesis or dissertation and its abstract are my original work, that they do not infringe or violate any rights of others, and that I make these grants as the sole owner of the rights to my thesis or dissertation and its abstract. I represent that I have obtained written permissions, when necessary, from the owner(s) of each third party copyrighted matter to be included in my thesis or dissertation and will supply copies of such upon request by my school. I acknowledge that RU ETD and my school will not distribute my thesis or dissertation or its abstract if, in their reasonable judgment, they believe all such rights have not been secured. I acknowledge that I retain ownership rights to the copyright of my work. I also retain the right to use all or part of this thesis or dissertation in future works, such as articles or books.
RightsEvent
DateTime (encoding = w3cdtf); (qualifier = exact); (point = start)
2017-10-31
DateTime (encoding = w3cdtf); (qualifier = exact); (point = end)
2019-10-31
Type
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Detail
Access to this PDF has been restricted at the author's request. It will be publicly available after October 31st, 2019.
Copyright
Status
Copyright protected
Availability
Status
Open
Reason
Permission or license
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