Serotonin 1a receptor mediated neurogenesis in the developing hippocampus
Item
-
Title
-
Serotonin 1a receptor mediated neurogenesis in the developing hippocampus
-
Identifier
-
d_2009_2013:f46b3c8729ee:10224
-
identifier
-
10398
-
Creator
-
Ranasinghe, Buddima,
-
Contributor
-
Probal Banerjee
-
Date
-
2009
-
Language
-
English
-
Publisher
-
City University of New York.
-
Subject
-
Neurosciences | Dentate Gyrus | Hippocampus | Neurogenesis | Retinoblastoma | Serotonin
-
Abstract
-
The importance of the brain serotonin 1A receptor (5-HT1A-R) during postnatal brain development has been established, but the mechanism of its action in brain neurons remains unclear. It is currently known that the 5-HT1A-R plays a crucial role in the brain by regulating mood and behavior and 5-HT1A-R stimulation in adult mice has been suggested to induce neurogenesis in the adult neurogenic niches such as the subventricular zone (SVZ) and the dentate gyrus (DG) of the hippocampus. In mice, absence of the 5-HT1A-R during development results in heightened anxiety and depressive behavior. However, the 5-HT1A-R mediated signaling activity that is responsible for its role during development is unknown. Among the hippocampal signaling pathways stimulated by the agonist-bound 5-HT 1A-R, the mitogen activated protein kinase (MAPK) pathway is an important regulator of both division and survival of neuronal cells in the brain. Additionally, the Protein Kinase C (PKC) isozyme PKCepsilon is an important signaling molecule that is highly expressed during early postnatal brain development particularly postnatal day 2-6 (P2-P6). Here we show that neurogenesis in the developing hippocampus at P6 in mice is dependent on both MAPK and PKCepsilon. Our initial experiments use pharmacological inhibitors to confirm that PKCepsilon mediates 5-HT1A-R-linked activation of MAPK. We then demonstrate that neurogenesis is increased upon stimulation of this 5-HT1A-R→→PKCepsilonMAPK pathway both in a hippocampal-derived neuronal cell line stably expressing the 5-HT1A-R (HN2-5) and in the DG of P6 mice. Further, inhibition of either MAPK or PKCepsilon considerably disrupts the burst in bromo-deoxy-uridine (BrdU) labeling and Ki-67 staining, showing neuroblast number, in the DG. As for a downstream signal that relays the proliferative signal from MAPK, we have identified the Retinoblastoma protein (Rb) as a potential target of MAPK, and shown that its phosphorylation dynamics may be tightly regulated in response to 5-HT1A-R stimulation. Therefore, our findings reveal a novel pathway involving PKCepsilon, MAPK, and Rb through which the 5-HT 1A-R potentially regulates neurogenesis during early postnatal hippocampal development.
-
Type
-
dissertation
-
Source
-
2009_2013.csv
-
degree
-
Ph.D.
-
Program
-
Biochemistry
