Deletion of IP₃ receptor2 in astrocytes enhances the hippocampal neurogenesis in adult mice

Abstract

[ACCESS RESTRICTED TO THE UNIVERSITY OF MISSOURI AT AUTHOR'S REQUEST.] Neurogenesis (birth of neurons) is a process by which neurons are generated from neural progenitor cells. It mainly occurs in two regions of brain, one is the sub-ventricular zone (SVZ) and the other is the subgranular zone (SGZ) in dentate gyrus of hippocampus. Astrocytes release calcium from intracellular stores in response to the activation of different types of Gq-linked G-protein-coupled receptors (GPCRs) through the binding of inositol 1, 4, 5-trisphosphate (IP3) to its receptor (IP3R). Astrocyte Ca[superscript 2+] has been deemed necessary and sufficient to trigger the release of glio-transmitters, such as ATP and glutamate, to modulate neuronal activity. Several lines of evidence suggest that IP3R type 2 (IP[subscript 3]R2) is the primary IP3R expressed in astrocytes. We already know that IP[subscript 3]R2 is a key mediator of astrocytic Ca[superscript 2+] dependent signaling cascades, but its role in neurogenesis is unknown. In this project, we use IP[subscript 3]R2 knockout mice (KO) mice to determine whether IP[subscript 3]R2 affects neuronal proliferation and survival in hippocampal SGZ. Using BrdU labeling method, we found that IP[subscript 3]R2 KO mice from age one to 3 month have an enhanced neuronal proliferation as compared with age-matched wild type (WT) mice. As IP[subscript 3]R2 is mainly expressed in astrocytes, our study suggests that astrocytes play an important role in adult neurogenesis through IP3R -mediated calcium signaling pathway. The overall results revealed that IP[subscript 3]R2 down regulated neurogenesis in adult mice hippocampus. Deletion of IP[subscript 3]R2 gene caused the proliferating GFAP+ stem cells, DCX+ immature neurons, and NeuN+ neurons increased. But decreased the number of microglia number in KO mice. Total survival proliferating cell number has a significant increase in 1.5 month old KO mice brain, and the increasing is a result of survival neurons, but not from other cell types. Finally the s100β+ horizontal glial cell number has a significantly reduction indicated that IP[subscript 3]R2 gene down regulated neurogenesis but up regulated gliogenesis.