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Assessing the GABA shift hypothesis through markers for oxidative stress, neuronal activity and microglia number following early VPA exposure
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Gifford, Janace. Assessing the GABA shift hypothesis through markers for oxidative stress, neuronal activity and microglia number following early VPA exposure. Retrieved from https://doi.org/doi:10.7282/t3-m082-f729

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TitleAssessing the GABA shift hypothesis through markers for oxidative stress, neuronal activity and microglia number following early VPA exposure
NameGifford, Janace (author); Wagner, George C (chair); Kusnecov, Alexander W (internal member); Samuels, Ben (internal member); Ming, Xue (outside member); Rutgers University; School of Graduate Studies
Date Created2021
Other Date2021-01 (degree)
SubjectAutism, GABA shift hypothesis, Autism spectrum disorders, GABA -- Agonists, Valproic acid, Psychology
Extent1 online resource (viii, 93 pages) : illustrations
DescriptionThe 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.
NotePh.D.
NoteIncludes bibliographical references
Genretheses, ETD doctoral
Persistent URLhttps://doi.org/doi:10.7282/t3-m082-f729
LanguageEnglish
CollectionSchool of Graduate Studies Electronic Theses and Dissertations
Organization NameRutgers, The State University of New Jersey
RightsThe author owns the copyright to this work.
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