Serotonin -1A receptor mediated signaling in neonatal hippocampal development.
Item
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Title
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Serotonin -1A receptor mediated signaling in neonatal hippocampal development.
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Identifier
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AAI3283196
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identifier
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3283196
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Creator
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Mehta, Mukti.
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Contributor
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Adviser: Probal Banerjee
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Date
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2007
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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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Biology, Neuroscience
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Abstract
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The brain serotonin 1A receptor (5-hydroxytryptamine- 1A-R) plays a crucial role in the modulation of emotional processes and is a target of medications used in the treatment of psychiatric disorders. Ablation of this receptor causes heightened anxiety in mice. Further studies have shown that the presence of post-synaptic hetero-5-HT1A-R (mainly in the hippocampus, septum and cortex), and not the autoreceptors (in the raphe) is essential between postnatal day-5--21 (P5--21) for the expression of normal anxiety levels in adult mice. Additionally, our earlier studies in differentiated HN2-5 cells (derived from hippocampal neurons) have shown that a 5-HT1A-R→ MAPK (Mitogen activated protein kinase) causes protection of these cells against apoptosis. Based on such observations and also considering that MAPK is linked to cell division we have postulated that the 5-HT1A-R→ MAPK cascade plays an important role in regulating neurogenesis and strengthening of synapses in the hippocampus during early post-natal development. Using cultured hippocampal slices from mice as a model, we studied 5-HT1A receptor-mediated specific responses during neonatal development. Our studies have revealed that at postnatal day-6 (P6) and day-15 (P15), 5-HT1A-R agonist (8-OH-DPAT) treatment causes activation of the MAPK isozymes ERK1/2 (extracellular signal-regulated kinases 1 and 2). Intriguingly, at P6, a PKC isozyme (probably protein kinase C-epsilon) was involved upstream of ERK1/2, whereas at P15, PKC-alpha was stimulated downstream of ERK1/2. Thus, the 5-HT1A-R-mediated stimulation of ERK1/2 in the hippocampus undergoes a transition between P6 and P15. At P6, a PKC isozyme is required for the 5-HT1A-R→ERK1/2 cascade, that upregulates cell division in the dentate gyrus. In contrast, at P15, PKCalpha participates downstream of ERK1/2 to mainly augment synaptic transmission through the Schaffer Collateral pathway. This temporal switch in the 5-HT 1A-R signaling uses PKC isozymes differentially, first boosting the cell division to form new hippocampal neurons to regulate neurogenesis at P6 and then undergoing a timely transitions in mechanism at P15 to strengthen synaptic connections that are probably essential for securing synaptic connections. Our overall objective has been to delineate transitions in 5-HT1A-R mediated signaling cascades and their functional effects on neonatal brain development.
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Type
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dissertation
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Source
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PQT Legacy CUNY.xlsx
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degree
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Ph.D.
