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Assessing the GABA shift hypothesis through markers for oxidative stress, neuronal activity and microglia number following early VPA exposure
Descriptive
TitleInfo
Title
Assessing the GABA shift hypothesis through markers for oxidative stress, neuronal activity and microglia number following early VPA exposure
Name
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Gifford
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Janace
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Janace Gifford
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author
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Wagner
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George C
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George C Wagner
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Advisory Committee
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chair
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(type = family)
Kusnecov
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Alexander W
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Alexander W Kusnecov
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Advisory Committee
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internal member
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(type = family)
Samuels
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(type = given)
Ben
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Ben Samuels
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Advisory Committee
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(authority = RULIB)
internal member
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(type = family)
Ming
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Xue
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Xue Ming
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Advisory Committee
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(authority = RULIB)
outside member
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Rutgers University
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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
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ETD doctoral
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2021
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2021-01
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English
Abstract
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The GABA-shift hypothesis proposes that GABA agonist action is excitatory early in development and transitions to an inhibitory role later in life. The present studies assessed the GABA-shift hypothesis in three distinct ways. First, if GABA is excitatory early in life, then administration of a GABA agonist should exert excitotoxic damage mediated by oxidative stress. Accordingly, valproic acid (VPA), an indirect-acting GABA agonist, was administered early in life or to adult mice and nuclear factor erythroid 2- related factor 2 (NRF2) expression was assessed. Activation of NRF2 initiates downstream antioxidant defense mechanisms. NRF2 activation was observed only in the young (prenatal and early postnatal) VPA-treated animals compared to young saline-treated controls and adult mice treated with VPA or saline. These observations support the hypothesis that VPA exerts excitatory effects mediated by oxidative stress only in young mice. The second objective of this study was to examine cFos expression before and after the GABA shift following exposure to VPA. cFos expression is considered a measure of cell activation so, once again, its activation was expected only in the younger mice. Here we observed no strong effect of early postnatal VPA treatment on c-fos expression. Upon review of the literature it was concluded that c-Fos may not be the best measure of neuronal activation in young mice. The third objective of the present study was to examine microglia number in distinct brain areas following early VPA exposure. Microglia number was observed 24 hours following treatment with VPA or saline. There was a differential response of microglia following VPA treatment throughout development and in distinct brain areas. More microglia cells were observed in the cerebellum following VPA treatment on P7, P14 and P30. In the hippocampus, increased microglia number was observed following VPA exposure at P7 but not later time points. These studies provide evidence of neurotoxic action of VPA potentially mediated by excitotoxicity. These results elucidate the critical importance and timing of GABA development as it might relate to the effects of GABA alterations and oxidative stress during early development.
Subject
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Topic
Autism
Subject
(authority = local)
Topic
GABA shift hypothesis
Subject
(authority = LCSH)
Topic
Autism spectrum disorders
Subject
(authority = LCSH)
Topic
GABA -- Agonists
Subject
(authority = LCSH)
Topic
Valproic acid
Subject
(authority = RUETD)
Topic
Psychology
RelatedItem
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Rutgers University Electronic Theses and Dissertations
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ETD_11342
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application/pdf
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text/xml
Extent
1 online resource (viii, 93 pages) : illustrations
Note
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Ph.D.
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Includes bibliographical references
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School of Graduate Studies Electronic Theses and Dissertations
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rucore10001600001
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NjNbRU
Identifier
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doi:10.7282/t3-m082-f729
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Rights
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The author owns the copyright to this work.
RightsHolder
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Name
FamilyName
Gifford
GivenName
Janace
Role
Copyright Holder
RightsEvent
Type
Permission or license
DateTime
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2020-12-16 09:44:46
AssociatedEntity
Name
Janace Gifford
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Copyright holder
Affiliation
Rutgers University. School of Graduate Studies
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Type
License
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Author Agreement License
Detail
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.
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Embargo
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2021-01-31
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2022-01-31
Detail
Access to this PDF has been restricted at the author's request. It will be publicly available after January 31st, 2022.
Copyright
Status
Copyright protected
Availability
Status
Open
Reason
Permission or license
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windows xp
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2021-01-22T15:40:33
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2021-01-22T15:40:33
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