Neurotransmitter-mediated control of neurogenesis in the adult vertebrate brain

Abstract

It was long thought that no new neurons are added to the adult brain. Similarly, neurotransmitter signaling was primarily associated with communication between differentiated neurons. Both of these ideas have been challenged, and a crosstalk between neurogenesis and neurotransmitter signaling is beginning to emerge. In this Review, we discuss neurotransmitter signaling as it functions at the intersection of stem cell research and regenerative medicine, exploring how it may regulate the formation of new functional neurons and outlining interactions with other signaling pathways. We consider evolutionary and cross-species comparative aspects, and integrate available results in the context of normal physiological versus pathological conditions. We also discuss the potential role of neurotransmitters in brain size regulation and implications for cell replacement therapies.

Keywords: Adult neurogenesis; Homeostasis; Neural stem cell; Neurotransmitter; Regeneration.

Fig. 1.

Neurotransmitter signaling and lineage. Alternative mechanisms for neurotransmitter-mediated regulation of cell fate. (A) Each neurotransmitter (NT) controls neurogenesis of its cognate subtype. If neural stem cells (NSCs) are multipotent, transmitters should act on amplifying populations and not on the multipotent stem cell. (B) Neurotransmitters control neurogenesis without subtype specificity, regulating proliferation and differentiation of progenitors but with subtype choices being determined by other factors. If NSCs are multipotent, transmitters could act on both NSCs and/or amplifying populations. (C) Each neurotransmitter controls neurogenesis of its cognate subtype. If NSCs have restricted potential, transmitters could act on both NSCs and/or amplifying populations. (D) Neurotransmitters control neurogenesis without subtype specificity. If NSCs have restricted potential, transmitters could act on both NSCs and/or amplifying populations. The different colors indicate different types of neurotransmitters produced by the neurons. Empty large circles, multipotent NSCs; filled small circles, NSCs with restricted fate; ovals, rectangles and triangles indicate amplifying populations.

Fig. 2.

Interactions between neurotransmitters and other signaling systems. Cell fate decisions during neurogenesis such as proliferation, differentiation and survival could be regulated by neurotransmitters directly (1) or indirectly through regulation of soluble factors (2) and their receptors (3). There are also data supporting the idea that growth factors regulate cell fate decisions through the release of neurotransmitters (4).

Fig. 3.

Negative control of neurogenesis. (A,B) The neurotransmitter produced directly regulates neurogenesis in a feedback-like manner, as seen in newt midbrain (A). Loss of neurons and consequent drop in neurotransmitter release allows quiescent cells to re-enter the cell cycle (B). (C,D) Neurons regulate neurogenesis through an intermediate neuronal subtype, as seen in the mammalian DG, where GABAergic interneurons inhibit proliferation of stem cells, which give rise to glutamatergic granule neurons. The high activity of the network with high GABA levels counteracts proliferation (C), whereas low activity leads to increased proliferation (D). GABA, γ-aminobutyric acid; NSC, neural stem cell.