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Neurotransmitter-Mediated Control of Neurogenesis in the Adult Vertebrate Brain Daniel A

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Neurotransmitter-Mediated Control of Neurogenesis in the Adult Vertebrate Brain Daniel A 2548 REVIEW Development 140, 2548-2561 (2013) doi:10.1242/dev.088005 © 2013. Published by The Company of Biologists Ltd Neurotransmitter-mediated control of neurogenesis in the adult vertebrate brain Daniel A. Berg1,2,*, Laure Belnoue3, Hongjun Song1,2,4 and András Simon3,* Summary Dictyostelium, indicating that the apparent antagonistic relationship It was long thought that no new neurons are added to the adult between glutamate and GABA signaling was established prior to brain. Similarly, neurotransmitter signaling was primarily the evolution of synaptic communication in the CNS. associated with communication between differentiated neurons. Furthermore, neurotransmitters control cell proliferation during Both of these ideas have been challenged, and a crosstalk development long before the onset of neurogenesis in mammals, as between neurogenesis and neurotransmitter signaling is exemplified by GABA signaling in the early embryo (Andäng et beginning to emerge. In this Review, we discuss al., 2008). Once developmental neurogenesis is initiated, neurotransmitter signaling as it functions at the intersection of neurotransmitter signaling has an impact on several aspects of stem cell research and regenerative medicine, exploring how it neurogenesis, including proliferation, migration and differentiation may regulate the formation of new functional neurons and in various locations in the CNS, such as the telencephalon, ventral outlining interactions with other signaling pathways. We midbrain and retina (Kim et al., 2006; Schlett, 2006; Heng et al., consider evolutionary and cross-species comparative aspects, and 2007; Martins and Pearson, 2008). In the lateral ganglionic integrate available results in the context of normal physiological eminence, for example, dopamine-mediated signaling influences versus pathological conditions. We also discuss the potential role proliferation of the dopamine receptor-expressing progenitor cells of neurotransmitters in brain size regulation and implications for (Diaz et al., 1997; Ohtani et al., 2003). cell replacement therapies. All these observations suggest that regulation of the cell cycle and cell differentiation is an ancient function of neurotransmitters Key words: Adult neurogenesis, Homeostasis, Neural stem cell, and that they may have been secondarily recruited to inter-neuronal Neurotransmitter, Regeneration communication during evolution. Thus, the control of neurogenesis – i.e. the progression of neural stem cells into functionally Introduction integrated mature neurons – may be a function of neurotransmitters In the brain, signaling via neurotransmitters, small molecules that is as significant as, but evolutionarily primordial to, their role released by neurons to communicate with other cells, has primarily in synaptic transmission. been associated with the function rather than with the formation of In this Review, we make an effort to integrate available data on neurons. However, several reports have identified roles for neurotransmitter-mediated control of adult neurogenesis in neurotransmitters in cell fate determination in a wide range of comparative settings: both across species and in normal species both within and outside the central nervous system (CNS). physiological versus pathological conditions, such as after injury A thorough discussion on the evolutionary origin of and during neurodegeneration. neurotransmitter signaling is outside the scope of this Review, but it is important to note that both neurotransmitters and their Cellular targets for neurotransmitter signaling in receptors (see Table 1) are present and functionally important in the brain organisms without a nervous system. For example, γ-aminobutyric New neurons are continuously created and functionally integrated acid (GABA), glutamate and nitric oxide (NO) have all been into existing neuronal networks in the adult brain. In almost all detected in sponges and shown to regulate cell behavior (Ellwanger mammals, active adult neurogenesis is confined to two distinct et al., 2007; Elliott and Leys, 2010). A recent transcriptome locations: the subventricular zone (SVZ) of the lateral ventricles in profiling of the sponge A. queenslandica revealed the expression of the forebrain; and the subgranular zone (SGZ) of the dentate gyrus wide repertoire of components active in synapses found in the (DG) in the hippocampus (Ming and Song, 2011). In the SGZ, vertebrate nervous systems (Conaco et al., 2012). In the social quiescent radial glial-like cells (RGLs) exhibit neural stem cell amoeba Dictysotelium, disruption of a glutamate receptor by (NSC) properties and give rise to proliferating neural progenitor homologous recombination reveals a role for glutamate signaling cells of transit amplifying characters, which eventually become in the suppression of cell division (Taniura et al., 2006), while neuroblasts and subsequently differentiate into mature neurons GABA induces terminal differentiation of spores through a GABAB (Malatesta et al., 2000; Noctor et al., 2001; Seri et al., 2004; receptor (Anjard and Loomis, 2006). GABA and glutamate appear Encinas et al., 2011; Bonaguidi et al., 2012). In this Review, we use to play opposing roles in spore induction (Fountain, 2010) in the somewhat sweeping term RGLs [cells with a radial glia morphology that express both nestin and glial fibrillary acidic protein (GFAP)] for both SGZ and SVZ precursor cells, even 1Institute for Cell Engineering, Johns Hopkins University School of Medicine, though these cells have rather different features in the SVZ versus Baltimore, MD 21287, USA. 2Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. 3Department of Cell and Molecular the SGZ (for a recent review, see Morrens et al., 2012). Biology, Karolinska Institute, Stockholm, SE-171 77, Sweden. 4The Solomon H. As in mammals, the brain of adult non-mammalian vertebrates, Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, such as fishes and amphibians, also harbors RGLs. Compared with Baltimore, MD 21287, USA. mammals, the distribution of proliferating RGLs is more *Authors for correspondence ([email protected]; [email protected]) widespread (Chernoff et al., 2003; Grandel et al., 2006; Berg et al., DEVELOPMENT Development 140 (12) REVIEW 2549 Table 1. Classification of neurotransmitters Neurotransmitter Receptor Type of receptor Cellular pathways References Selective cation channel (Itier and Nicotinic receptor composed of five protein Bertrand, 2001 subunits , , , and Acetylcholine Muscarinic M1, M3 G protein-coupled receptor GqPLCIP3+DAG and M5 receptors (Eglen et al., (Muscarinic M2 and M4 GiٜACcAMP 2006 G protein-coupled receptor receptors GK+ channel opening Cation channel, composed of a (Gasic and heterotetramer of GluA1, AMPA receptor Heinemann GluA2, GluA3 and GluA4 1991) subunits High Ca2+ permeability, voltage- dependant Mg2+ block channel, (Mc Bain et al., NMDA receptor composed of a heterotetramer 1994) of NR1, NR2 and NR3 subunits Cation channel, composed of a (Hollmann and Glutamate Kainate receptor heterotetramer of GluK1, GluK2, Heinemann, GluK3 and Gluk4 1994) Group I: mGluR1 and Amino acids G protein-coupled receptor GqPLCIP3+DAG mGluR5 receptors Group II: mGluR2 and (Benarroch et mGluR3 receptors GiٜACcAMP al., 2008) Group III: mGluR4, G protein-coupled receptor GK+ channel opening mGluR6, mGluR7 and and Ca2+ channel closing mGluR8 receptors GABAA receptor (Sieghart and Selective chloric channel, Sperk, 2002; composed of five subunits (from GABAC receptor Benarroch et GABA up to 17 different subunits) al., 2007) GiٜACcAMP (Benarroch et GABAB receptor G protein-coupled receptor GK+ channel opening al., 2012) 5-HT3 receptor Cation channel GiٜACcAMP 5-HT1 receptor G protein-coupled receptor GK+ channel opening (Benarroch et Serotonin (5-HT) 5-HT2 receptor G protein-coupled receptor GqPLCIP3+DAG al., 2009b) 5-HT5 receptor G protein-coupled receptor GiٜACcAMP 5-HT4, 5-HT6 and G protein-coupled receptor GiACcAMP 5-HT7 receptors D1-like receptor: D1 G protein-coupled receptor GiACcAMP and D5 receptors (Neve et al., Dopamine GiٜACcAMP Monoamines D2-like receptor: D2, 2004) G protein-coupled receptor GK+ channel opening D3 and D4 receptors and Ca2+ channel closing 1-adrenoreceptors: 1A, 1B and 1C G protein-coupled receptor GqPLCIP3+DAG receptors 2-adrenoreceptors: (Hieble et al., Noradrenaline (2A, 2B and 2C G protein-coupled receptor GiٜACcAMP 2007 receptors 1-adrenoreceptors: G protein-coupled receptor GiACcAMP 1 and 2 receptors GiٜACcAMP (Benarroch et GK+ channel opening Neuroactive Y1, Y2, Y4, Y5 al., 2009a; Sah Neuropeptide Y G protein-coupled receptor and Ca2+ channel closing peptides receptor and Geracioti, GPIP3ERK 2012) GPLCERK (Ignarro et al., Soluble gases Nitric oxide Liposoluble GGCcGMP 1989; Guix et al., 2005) Neurotransmitters can be subdivided into five main categories: cations, amino acids, monoamines, neuroactive peptides and soluble gases. The table summarizes different neurotransmitters, their receptors and the pathways implicated in their signaling transduction. This list is not exhaustive, we present only neurotransmitters implicated in modulating adult neurogenesis. Neurotransmitters can bind to ionotropic or metabotropic receptors. Ionotropic receptors regulate ion channels; metabotropic receptors are G-protein coupled. 5-HT, 5-hydroxytryptamine (serotonin); AC, adenylate cyclase; AMPA, 2-amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl)propanoic acid; DAG, diacylglycerol; ERK, extracellular-
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