The Role of Serotonin 1A Receptor-Mediated Signaling in PSD95 Induction and Synaptogenesis during Neonatal Hippocampal Development
Item
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Title
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The Role of Serotonin 1A Receptor-Mediated Signaling in PSD95 Induction and Synaptogenesis during Neonatal Hippocampal Development
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Identifier
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d_2009_2013:951954946607:11079
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identifier
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11318
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Creator
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Mogha, Amit,
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Contributor
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Probal Banerjee
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Date
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2011
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Language
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English
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Publisher
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City University of New York.
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Subject
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Neurosciences | Molecular biology | Developmental biology | Anxiety | Development | Hippocampus | PSD95 | Serotonin 1A Receptor | Synaptogenesis
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Abstract
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Previous studies have shown that the 5-HT1A-R is essential for neonatal front brain development. A polymorphism in 5-HT1A-R gene leading to its aberrant expression has been reported to result in severe depression in humans, while its absence up to postnatal day 15 (P15) results in anxiety like behavior in mice. How this receptor functions to regulate the behavior of an animal is still poorly understood. Our prior studies have shown that 5-HT1A-R mediated signaling pathway leads to stimulation of a neuro-protective MAPK→PKC&agr; pathway in differentiated hippocampal neuron-derived HN2-5 cells. Further studies showed that this pathway is also functional in cultured P15 hippocampal slices and that it causes an induction in field EPSP (fEPSP) in the P15 slices. To further understand the mechanistic role of 5-HT1A-R in synaptogenesis we used organotypic hippocampal slice cultures from C57BL6 mice at P15 to show that the activation of 5-HT 1A-R mediated signaling pathway in the hippocampus leads to a massive increase in PSD95 expression and dendritic spine as well as synapse number. The results presented in our study demonstrate that 5-HT1A-R mediated signaling pathway acts via sequential activation of ERK and PKC. In vivo studies by intrahippocampally infusing 5-HT1A-R agonist and different signaling inhibitors revealed that the same pathway is involved in the induction of PSD95 and synaptogenesis in vivo via activation of PKC&agr; in C57 as well as Swiss Webster mice. We further demonstrated that intra-hippocampal infusion of antidepressant drug like Fluoxetine, which is Selective Serotonin Reuptake Inhibitor (SSRI), leads to the induction of PSD95 and synaptogenesis through the same pathway. Equipped with this knowledge, we activated the 5-HT 1A-R mediated signaling pathway in 5-HT1A-R (-/-) mice by activating the downstream effector PKC&agr; by intrahippocampally infusing its activator Bryostatin, which is also an Alzheimer's drug, to boost PSD95 expression and synaptogenesis. We also observed that the 5-HT1A-R (-/-) mice have less number of synapses in the hippocampus. We, therefore for the first time elucidate the signaling pathway which explains how 5-HT 1A-R regulates hippocampal sculpting and function, which may determine the affective normalcy of an adult.
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Type
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dissertation
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Source
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2009_2013.csv
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degree
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Ph.D.
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Program
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Biology
