Opposing effects of α2- and β-adrenergic receptor stimulation on quiescent neural precursor cell activity and adult hippocampal neurogenesis.

Dhanisha J Jhaveri,Ishira Nanavaty,Steven G Kernie,Basma F A Husain,Boris W Prosper,Swanand Marathe,Vidita A Vaidya,Perry F Bartlett,Pierre Gressens

doi:10.1371/journal.pone.0098736

Abstract

Norepinephrine regulates latent neural stem cell activity and adult hippocampal neurogenesis, and has an important role in modulating hippocampal functions such as learning, memory and mood. Adult hippocampal neurogenesis is a multi-stage process, spanning from the activation and proliferation of hippocampal stem cells, to their differentiation into neurons. However, the stage-specific effects of noradrenergic receptors in regulating adult hippocampal neurogenesis remain poorly understood. In this study, we used transgenic Nestin-GFP mice and neurosphere assays to show that modulation of α2- and β-adrenergic receptor activity directly affects Nestin-GFP/GFAP-positive precursor cell population albeit in an opposing fashion. While selective stimulation of α2-adrenergic receptors decreases precursor cell activation, proliferation and immature neuron number, stimulation of β-adrenergic receptors activates the quiescent precursor pool and enhances their proliferation in the adult hippocampus. Furthermore, our data indicate no major role for α1-adrenergic receptors, as we did not observe any change in either the activation and proliferation of hippocampal precursors following selective stimulation or blockade of α1-adrenergic receptors. Taken together, our data suggest that under physiological as well as under conditions that lead to enhanced norepinephrine release, the balance between α2- and β-adrenergic receptor activity regulates precursor cell activity and hippocampal neurogenesis.

Highlights

The mammalian hippocampal neurogenic niche retains quiescent neural precursor cells that generate newborn neurons throughout life [1,2]
Our in vitro neurosphere assay results, as well as the in vivo findings from administration of adrenergic receptor-selective agonists and antagonists, demonstrate that a2- and b-adrenergic receptors exert direct and opposing effects on the regulation of quiescent neural precursor cell activity, whereas a1-adrenergic receptors do not appear to have a significant role in the regulation of adult hippocampal neurogenesis
The demonstration that guanabenz significantly decreased the number of neurospheres, as well as the number of BrdU-positive cells in the subgranular zone (SGZ), suggests that a2-adrenergic receptors expressed by hippocampal precursors play an inhibitory role in regulating the cell cycle

Summary

Introduction

The mammalian hippocampal neurogenic niche retains quiescent neural precursor cells that generate newborn neurons throughout life [1,2] This process of adult hippocampal neurogenesis is a unique form of structural plasticity that has been implicated in the regulation of hippocampus-specific cognitive and mood-related functions [3,4]. Our results indicate no major role for the a1-adrenergic receptor in regulating adult hippocampal neurogenesis. These findings reveal that norepinephrine acts through the a2- and b-adrenergic receptors to exert a direct but opposing effect on quiescent neural precursor cell activity and hippocampal neurogenesis

Materials and Methods

Results

Discussion