Neurotransmitter-mediated control of neurogenesis in the adult vertebrate brain

Abstract

SummaryIt 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. Key words: Adult neurogenesis, Homeostasis, Neural stem cell, Neurotransmitter, Regeneration IntroductionIn the brain, signaling via neurotransmitters, small molecules released by neurons to communicate with other cells, has primarily been associated with the function rather than with the formation of neurons. However, several reports have identified roles for neurotransmitters in cell fate determination in a wide range of species both within and outside the central nervous system (CNS). A thorough discussion on the evolutionary origin of neurotransmitter signaling is outside the scope of this Review, but it is important to note that both neurotransmitters and their receptors (see Table 1) are present and functionally important in organisms without a nervous system. For example, γ-aminobutyric acid (GABA), glutamate and nitric oxide (NO) have all been detected in sponges and shown to regulate cell behavior (Ellwanger et al., 2007;Elliott and Leys, 2010). A recent transcriptome profiling of the sponge A. queenslandica revealed the expression of wide repertoire of components active in synapses found in the vertebrate nervous systems (Conaco et al., 2012). In the social amoeba Dictysotelium, disruption of a glutamate receptor by homologous recombination reveals a role for glutamate signaling in the suppression of cell division (Taniura et al., 2006), while GABA induces terminal differentiation of spores through a GABA B receptor (Anjard and Loomis, 2006). GABA and glutamate appear to play opposing roles in spore induction (Fountain, 2010) in Dictyostelium, indicating that the apparent antagonistic relationship between glutamate and GABA signaling was established prior to the evolution of synaptic communication in the CNS.Furthermore, neurotransmitters control cell proliferation during development long before the onset of neurogenesis in mammals, as exemplified by GABA signaling in the early embryo (Andäng et al., 2008). Once developmental neurogenesis is initiated, neurotransmitter signaling has an impact on several aspects of neurogenesis, including proliferation, migration and differentiation in various locations in the CNS, such as the tele...

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