Abstract
Adult neurogenesis is the process of creating new brain cells during adulthood. This involves several stages including proliferation, migration, differentiation, integration, and survival. G-protein-coupled receptors (GPCRs) regulate this process in both neurogenic regions of the brain: the subgranular and subventricular zones. The regulation of adult neurogenesis by GPCRs holds therapeutic promise for many neuropathologies. Several GPCRs activated by the neurotransmitters dopamine, glutamate, norepinephrine, and serotonin were shown to regulate adult neurogenesis. Melatonin, a neurohormone, and inflammatory molecules such as chemokines and prostaglandins modulate different stages of neurogenesis through GPCRs as well. The methods for studying the adult neurogenic stages depend upon labeling of dividing cells using the synthetic thymidine analog, nucleoside 5-bromo-2′-deoxyuridine (BrdU). BrdU incorporates into the DNA, is transferred to daughter cells, and is labeled using antibodies. The length of time after injection determines which stage of neurogenesis is being examined. Additional methods include culture of neonatal or adult neurospheres isolated from the subventricular zone, monolayer cultures of isolated neural stem cells, as well as transgenic manipulations via standard or viral-mediated techniques. In recent years, the use of Cre-inducible transgenic animals has developed and led to the creation of double- and triple-transgenic animals with specific activation of receptors in selected cell types. Future work in GPCR regulation of adult neurogenesis will likely include the use of opsin-receptor chimeras allowing precise spatial and temporal activation of GPCRs in neural stem/progenitor cells via optogenetics. This chapter summarizes the roles of various GPCRs involved in the regulation of adult neural stem cells and their progenitors and the current methods used to examine the actions of GPCRs in adult neurogenesis.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Similar content being viewed by others
References
Sanai N, Tramontin AD, Quiñones-Hinojosa A et al (2004) Unique astrocyte ribbon in adult human brain contains neural stem cells but lacks chain migration. Nature 427:740–744
Kam M, Curtis MA, McGlashan SR et al (2009) The cellular composition and morphological organization of the rostral migratory stream in the adult human brain. J Chem Neuroanat 37:196–205
Winner B, Cooper-Kuhn CM, Aigner R et al (2002) Long-term survival and cell death of newly generated neurons in the adult rat olfactory bulb. Eur J Neurosci 16:1681–1689
Petreanu L, Alvarez-Buylla A (2002) Maturation and death of adult-born olfactory bulb granule neurons: role of olfaction. J Neurosci 22:6106–6113
Dayer AG, Ford AA, Cleaver KM et al (2003) Short-term and long-term survival of new neurons in the rat dentate gyrus. J Comp Neurol 460:563–572
Kuipers SD, Tiron A, Soule J et al (2009) Selective survival and maturation of adult-born dentate granule cells expressing the immediate early gene Arc/Arg3.1. PLoS One 4:e4885
Shors TJ, Anderson ML, Curlik DM et al (2012) Use it or lose it: how neurogenesis keeps the brain fit for learning. Behav Brain Res 227:450–458
Ge S, Pradhan DA, Ming G-L et al (2007) GABA sets the tempo for activity-dependent adult neurogenesis. Trends Neurosci 30:1–8
Altman J, Das GD (1965) Autoradiographic and histological evidence of postnatal hippocampal neurogenesis in rats. J Comp Neurol 124:319–335
Taghipour M, Razmkon A (2012) Isolation and growth of neural stem cells derived from adult human hippocampus. J Inj Violence Res 4:S1
Höglinger GU, Rizk P, Muriel MP et al (2004) Dopamine depletion impairs precursor cell proliferation in Parkinson disease. Nat Neurosci 7:726–735
O’Keeffe G, Barker RA, Caldwell MA (2009) Dopaminergic modulation of neurogenesis in the subventricular zone of the adult brain. Cell Cycle 8:2888–2894
Diaz J, Ridray S, Mignon V et al (1997) Selective expression of dopamine D3 receptor mRNA in proliferative zones during embryonic development of the rat brain. J Neurosci 17:4282–4292
Araki KY, Sims JR, Bhide PG (2007) Dopamine receptor mRNA and protein expression in the mouse corpus striatum and cerebral cortex during pre- and postnatal development. Brain Res 1156:31–45
Coronas V, Bantubungi K, Fombonne J et al (2004) Dopamine D3 receptor stimulation promotes the proliferation of cells derived from the post-natal subventricular zone. J Neurochem 91:1292–1301
Lao CL, Lu CS, Chen JC (2013) Dopamine D(3) receptor activation promotes neural stem/progenitor cell proliferation through AKT and ERK1/2 pathways and expands type-B and-C cells in adult subventricular zone. Glia 61:475–489
Van Kampen JM, Hagg T, Robertson HA (2004) Induction of neurogenesis in the adult rat subventricular zone and neostriatum following dopamine D3 receptor stimulation. Eur J Neurosci 19:2377–2387
Kim Y, Wang W-Z, Comte I et al (2010) Dopamine stimulation of postnatal murine subventricular zone neurogenesis via the D3 receptor. J Neurochem 114:750–760
Baker SA, Baker KA, Hagg T (2005) D3 dopamine receptors do not regulate neurogenesis in the subventricular zone of adult mice. Neurobiol Dis 18:523–527
Egeland M, Zhang X, Millan MJ et al (2012) Pharmacological or genetic blockade of the dopamine D3 receptor increases cell proliferation in the hippocampus of adult mice. J Neurochem 123:811–823
Luján R, Nusser Z, Roberts J et al (1996) Perisynaptic location of metabotropic glutamate receptors mGluR1 and mGluR5 on dendrites and dendritic spines in the rat hippocampus. Eur J Neurosci 8:1488–1500
Simonyi A, Ngomba RT, Storto M et al (2005) Expression of groups I and II metabotropic glutamate receptors in the rat brain during aging. Brain Res 1043:95–106
Castiglione M, Calafiore M, Costa L et al (2008) Group I metabotropic glutamate receptors control proliferation, survival and differentiation of cultured neural progenitor cells isolated from the subventricular zone of adult mice. Neuropharmacology 55:560–567
Zhao L, Jiao Q, Chen X et al (2012) mGluR5 is involved in proliferation of rat neural progenitor cells exposed to hypoxia with activation of mitogen-activated protein kinase signaling pathway. J Neurosci Res 90:447–460
Ciceroni C, Mosillo P, Mastrantoni E et al (2010) mGLU3 metabotropic glutamate receptors modulate the differentiation of subventricular zone-derived neural stem cells towards the astrocytic lineage. Glia 58:813–822
Tian Y, Liu Y, Chen X et al (2010) AMN082 promotes the proliferation and differentiation of neural progenitor cells with influence on phosphorylation of MAPK signaling pathways. Neurochem Int 57:8–15
Wu D, Katz A, Lee C et al (1992) Activation of phospholipase C by alpha1-adrenergic receptors is mediated by the alpha subunits of Gq family. J Bio Chem 267:25798–25802
Gurdal H, Seasholtz T, Wang H et al (1997) Role of Gαq or Gαo proteins in α1-adrenoceptor subtype-mediated responses in Fischer 344 rat aorta. Mol Pharmacol 52:1064–1070
Papay RS, Gaivin RJ, Jha A et al (2006) Localization of the mouse α1A-adrenergic receptor (AR) in the brain: α1AAR is expressed in neurons, GABAergic interneurons, and NG2 oligodendrocyte progenitors. J Comp Neurol 497:209–222
Gupta MK, Papay RS, Jurgens CWD et al (2009) α1-adrenergic receptors regulate neurogenesis and gliogenesis. Mol Pharmacol 76:314
Wang R, Macmillan LB, Fremeau RT et al (1996) Expression of alpha 2-adrenergic receptor subtypes in the mouse brain: evaluation of spatial and temporal information imparted by 3 kb of 5′ regulatory sequence for the alpha 2A AR-receptor gene in transgenic animals. Neuroscience 74:199–218
Karkoulias G, Mastrogianni O, Ilias I et al (2006) Alpha 2-adrenergic receptors decrease DNA replication and cell proliferation and induce neurite outgrowth in transfected rat pheochromocytoma cells. Ann N Y Acad Sci 1088:335–345
Taraviras S, Olli-Lähdesmäki T, Lymperopoulos A et al (2002) Subtype-specific neuronal differentiation of PC12 cells transfected with alpha2-adrenergic receptors. Eur J Cell Biol 81:363–374
Yanpallewar SU, Fernandes K, Marathe SV et al (2010) Alpha2-adrenoceptor blockade accelerates the neurogenic, neurotrophic, and behavioral effects of chronic antidepressant treatment. J Neurosci 30:1096–1109
Rizk P, Salazar J, Raisman-Vozari R et al (2006) The alpha2-adrenoceptor antagonist dexefaroxan enhances hippocampal neurogenesis by increasing the survival and differentiation of new granule cells. Neuropsychopharmacology 31:1146–1157
Masuda T, Nakagawa S, Boku S et al (2012) Noradrenaline increases neural precursor cells derived from adult rat dentate gyrus through β2 receptor. Prog Neuropsychopharmacol Biol Psychiatry 36:44–51
Jhaveri DJ, Mackay EW, Hamlin AS et al (2010) Norepinephrine directly activates adult hippocampal precursors via beta3-adrenergic receptors. J Neurosci 30:2795–2806
Aghajanian GK, Sanders-Bush E (2002) Serotonin. In: Davis KL, Charney D, Coyle JT et al (eds) Neuropsychopharmacology: the fifth generation of progress. Lippincott Williams & Wilkins, Philadelphia
Klempin F, Babu H, De Pietri Tonelli D et al (2010) Oppositional effects of serotonin receptors 5-HT1a, 2, and 2c in the regulation of adult hippocampal neurogenesis. Front Mol Neurosci 3:1–11
Arnold SA, Hagg T (2012) Serotonin 1A receptor agonist increases species-and region-selective adult CNS proliferation, but not through CNTF. Neuropharmacology 63:1238–1247
Banasr M, Hery M, Printemps R et al (2004) Serotonin-induced increases in adult cell proliferation and neurogenesis are mediated through different and common 5-HT receptor subtypes in the dentate gyrus and the subventricular zone. Neuropsychopharmacology 29:450–460
Huang G-J, Herbert J (2005) The role of 5-HT1A receptors in the proliferation and survival of progenitor cells in the dentate gyrus of the adult hippocampus and their regulation by corticoids. Neuroscience 135:803–813
Soumier A, Banasr M, Lortet S et al (2009) Mechanisms contributing to the phase-dependent regulation of neurogenesis by the novel antidepressant, agomelatine, in the adult rat hippocampus. Neuropsychopharmacology 34:2390–2403
Radley JJ, Jacobs BL (2002) 5-HT1A receptor antagonist administration decreases cell proliferation in the dentate gyrus. Brain Res 955:264–267
Santarelli L, Saxe M, Gross C et al (2003) Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Science 301(80):805–809
Soumier A, Banasr M, Goff LK-L et al (2010) Region- and phase-dependent effects of 5-HT(1A) and 5-HT(2C) receptor activation on adult neurogenesis. Eur Neuropsychopharmacol 20:336–345
Xia L, Deloménie C, David I et al (2012) Ventral hippocampal molecular pathways and impaired neurogenesis associated with 5-HT 1A and 5-HT 1B receptors disruption in mice. Neurosci Lett 521:20–25
Gustafson EL, Durkin MM, Bard JA et al (1996) A receptor autoradiographic and in situ hybridization analysis of the distribution of the 5-ht7 receptor in rat brain. Br J Pharmacol 117:657–666
Martín-Cora FJ, Pazos A (2004) Autoradiographic distribution of 5-HT7 receptors in the human brain using [3H]mesulergine: comparison to other mammalian species. Br J Pharmacol 141:92–104
Bonaventure P, Nepomuceno D, Kwok A et al (2002) Reconsideration of 5-hydroxytryptamine (5-HT)(7) receptor distribution using [(3)H]5-carboxamidotryptamine and [(3)H]8-hydroxy-2-(di-n-propylamino)tetraline: analysis in brain of 5-HT(1A) knock-out and 5-HT(1A/1B) double-knock-out mice. J Pharmacol Exp Ther 302:240–248
Neumaier JF, Sexton TJ, Yracheta J et al (2001) Localization of 5-HT(7) receptors in rat brain by immunocytochemistry, in situ hybridization, and agonist stimulated cFos expression. J Chem Neuroanat 21:63–73
Xu H, Chen Z, He J et al (2006) Synergetic effects of quetiapine and venlafaxine in preventing the chronic restraint stress-induced decrease in cell proliferation and BDNF expression in rat hippocampus. Hippocampus 16:551–559
Musshoff U, Riewenherm D, Berger E et al (2002) Melatonin receptors in rat hippocampus: molecular and functional investigations. Hippocampus 12:165–173
Sotthibundhu A, Phansuwan-Pujito P, Govitrapong P (2010) Melatonin increases proliferation of cultured neural stem cells obtained from adult mouse subventricular zone. J Pineal Res 49:291–300
Ramirez-Rodriguez G, Ortíz-López L, Domínguez-Alonso A et al (2011) Chronic treatment with melatonin stimulates dendrite maturation and complexity in adult hippocampal neurogenesis of mice. J Pineal Res 50:29–37
Ramírez-Rodríguez G, Vega-Rivera NM, Benítez-King G et al (2012) Melatonin supplementation delays the decline of adult hippocampal neurogenesis during normal aging of mice. Neurosci Lett 530:53–58
Ramírez-Rodríguez G, Klempin F, Babu H et al (2009) Melatonin modulates cell survival of new neurons in the hippocampus of adult mice. Neuropsychopharmacology 34:2180–2191
Fava M, Targum SD, Nierenberg AA et al (2012) An exploratory study of combination buspirone and melatonin SR in major depressive disorder (MDD): a possible role for neurogenesis in drug discovery. J Psychiatr Res 46:1553–1563
Lu M, Grove EA, Miller RJ (2002) Abnormal development of the hippocampal dentate gyrus in mice lacking the CXCR4 chemokine receptor. Proc Natl Acad Sci U S A 99:7090–7095
Bagri A, Gurney T, He X et al (2002) The chemokine SDF1 regulates migration of dentate granule cells. Development 129:4249–4260
Bhattacharyya BJ, Banisadr G, Jung H et al (2008) The chemokine stromal cell-derived factor-1 regulates GABAergic inputs to neural progenitors in the postnatal dentate gyrus. J Neurosci 28:6720–6730
Dziembowska M, Tham TN, Lau P et al (2005) A role for CXCR4 signaling in survival and migration of neural and oligodendrocyte precursors. Glia 50:258–269
Kolodziej A, Schulz S, Guyon A et al (2008) Tonic activation of CXC chemokine receptor 4 in immature granule cells supports neurogenesis in the adult dentate gyrus. J Neurosci 28:4488–4500
Chizzolini C, Brembilla NC (2009) Prostaglandin E2: igniting the fire. Immunol Cell Biol 87:510–511
Chen C, Magee JC, Bazan NG (2002) Cyclooxygenase-2 regulates prostaglandin E2 signaling in hippocampal long-term synaptic plasticity. J Neurophysiol 87:2851–2857
Uchida K, Kumihashi K, Kurosawa S et al (2002) Stimulatory effects of prostaglandin E2 on neurogenesis in the dentate gyrus of the adult rat stimulatory effects of prostaglandin E2 on neurogenesis in the dentate gyrus of the adult rat. Zoolog Sci 19:1211–1216
Sasaki T, Kitagawa K, Sugiura S et al (2003) Implication of cyclooxygenase-2 on enhanced proliferation of neural progenitor cells in the adult mouse hippocampus after ischemia. J Neurosci Res 72:461–471
Kumihashi K, Uchida K, Miyazaki H et al (2001) Acetylsalicylic acid reduces ischemia-induced proliferation of dentate cells in gerbils. Neuroreport 12:915–917
Thomas née Williams SA, Segal MB (1996) Identification of a saturable uptake system for deoxyribonucleosides at the blood–brain and blood-cerebrospinal fluid barriers. Brain Res 741:230–239
Cameron H, McKay RD (2001) Adult neurogenesis produces a large pool of new granule cells in the dentate gyrus. J Comp Neurol 435:406–417
Parent JM, Yu TW, Leibowitz RT et al (1997) Dentate granule cell neurogenesis is increased by seizures and contributes to aberrant network reorganization in the adult rat hippocampus. J Neurosci 17:3727–3738
Olariu A, Cleaver KM, Shore LE et al (2005) A natural form of learning can increase and decrease the survival of new neurons in the dentate gyrus. Hippocampus 15:750–762
Van Praag H, Kempermann G, Gage FH (1999) Running increases cell proliferation and neurogenesis in the adult mouse dentate gyrus. Nat Neurosci 2:266–270
Kuhn HG, Dickinson-Anson H, Gage FH (1996) Neurogenesis in the dentate gyrus of the adult rat: age-related decrease of neuronal progenitor proliferation. J Neurosci 16:2027–2033
Kempermann G, Gage FH (2002) Genetic influence on phenotypic differentiation in adult hippocampal neurogenesis. Brain Res Dev Brain Res 134:1–12
Mathews EA, Morgenstern NA, Piatti VC et al (2010) A distinctive layering pattern of mouse dentate granule cells is generated by developmental and adult neurogenesis. J Comp Neurol 518:4479–4490
Hockfield S, Carlson S, Evans C et al (1993) Immunocytochemistry. In: Selected methods for antibody and nucleic acid probes. Cold Spring Harbor Laboratory Press, Plainview
Gage GJ, Kipke DR, Shain W (2012) Whole animal perfusion fixation for rodents (video). J Vis Exp 30:3564
Franklin G, Paxinos KBJ (2003) The mouse brain in stereotaxic coordinates, 2nd edn. Academic Press/Elsevier, Amsterdam
Slomianka L, West MJ (2005) Estimators of the precision of stereological estimates: an example based on the CA1 pyramidal cell layer of rats. Neuroscience 136:757–767
Peltier J, Schaffer DV (2010) Viral packaging and transduction of adult hippocampal neural progenitors. Methods Mol Biol 621:103–116
Kiyota T, Ingraham KL, Swan RJ et al (2012) AAV serotype 2/1-mediated gene delivery of anti-inflammatory interleukin-10 enhances neurogenesis and cognitive function in APP+PS1 mice. Gene Ther 19:724–733
Lee N, Batt MK, Cronier BA et al (2013) Ciliary neurotrophic factor receptor regulation of adult forebrain neurogenesis. J Neurosci 33:1241–1258
Pastrana E, Silva-Vargas V, Doetsch F (2011) Eyes wide open: a critical review of sphere-formation as an assay for stem cells. Cell Stem Cell 8:486–498
Azari H, Rahman M, Sharififar S et al (2010) Isolation and expansion of the adult mouse neural stem cells using the neurosphere assay. J Vis Exp 45:2–5
Babu H, Claasen J-H, Kannan S et al (2011) A protocol for isolation and enriched monolayer cultivation of neural precursor cells from mouse dentate gyrus. Front Neurosci 5:10
Airan RD, Thompson KR, Fenno LE et al (2009) Temporally precise in vivo control of intracellular signalling. Nature 458:1025–1029
Acknowledgments
This work was supported in part by the National Science Foundation [Grant 0347259]; the National Institutes of Health National Center for Research Resources [Grant P20RR016471]; the National Heart, Lung, and Blood Institute [Grant R01HL098279]; and the American Heart Association [Grant-in-Aid, Great Rivers Affiliate]. No conflicts of interest are noted.
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2014 Springer Science+Business Media New York
About this protocol
Cite this protocol
Collette, K.M., Doze, V.A., Perez, D.M. (2014). The Role of G-Protein-Coupled Receptors in Adult Neurogenesis. In: Stevens, C. (eds) G Protein-Coupled Receptor Genetics. Methods in Pharmacology and Toxicology. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-62703-779-2_21
Download citation
DOI: https://doi.org/10.1007/978-1-62703-779-2_21
Published:
Publisher Name: Humana Press, Totowa, NJ
Print ISBN: 978-1-62703-778-5
Online ISBN: 978-1-62703-779-2
eBook Packages: Springer Protocols