Neurotransmitter signaling in postnatal neurogenesis: The first leg

Abstract

Like the liver or other peripheral organs, two regions of the adult brain possess the ability of self-renewal through a process called neurogenesis. This raises tremendous hope for repairing the damaged brain, and it has stimulated research on identifying signals controlling neurogenesis. Neurogenesis involves several stages from fate determination to synaptic integration via proliferation, migration, and maturation. While fate determination primarily depends on a genetic signature, other stages are controlled by the interplay between genes and microenvironmental signals. Here, we propose that neurotransmitters are master regulators of the different stages of neurogenesis. In favor of this idea, a description of selective neurotransmitter signaling and their functions in the largest neurogenic zone, the subventricular zone (SVZ), is provided. In particular, we emphasize the interactions between neuroblasts and astrocyte-like cells that release gamma-aminobutyric acid (GABA) and glutamate, respectively. However, we also raise several limitations to our knowledge on neurotransmitters in neurogenesis. The function of neurotransmitters in vivo remains largely unexplored. Neurotransmitter signaling has been viewed as uniform, which dramatically contrasts with the cellular and molecular mosaic nature of the SVZ. How neurotransmitters are integrated with other well-conserved molecules, such as sonic hedgehog, is poorly understood. In an effort to reconcile these differences, we discuss how specificity of neurotransmitter functions can be provided through their multitude of receptors and intracellular pathways in different cell types and their possible interactions with sonic hedgehog.

Figure 1. Structure of the neurogenic subventricular zone

(a) Reconstruction of a sagittal slice of a postnatal (P) 25 mouse brain immunostained for doublecortin (DCX). Chains of DCX-expressing neuroblasts from the subventricular zone (SVZ) converge to form the rostral migratory stream (RMS), which terminates in the olfactory bulb. Scale bar: 500 μm. (b) Simplified diagram illustrating the cellular composition of the SVZ. The processes of a SVZ astrocyte ensheath a cluster of neuroblasts (in a coronal plan).

Figure 2. GABAergic and glutamatergic signaling in the SVZ

(a) Confocal photograph displaying co-immunostaining for glutamate (green), GLAST (glutamate-aspartate transporter) which labels astrocytes (red), and DCX (a marker of neuroblasts, blue) in the rostral extension of the SVZ. Scale bar: 10 μm. (b) Model illustrating that FLRFa peptide induces calcium increases in RMS astrocytes leading to glutamate release and NMDA receptor activation in adjacent neuroblasts recorded with a patch clamp pipette. (c) Simplified diagram illustrating the expression of GABA and glutamate signaling molecules in the SVZ. Neuroblasts can release GABA into the extracellular space. GABA activates GABA_A receptors in SVZ astrocytes. Upon intracellular calcium increase, glutamate is released by SVZ astrocytes. Released glutamate diffuses and activates glutamate receptors on neuroblasts.