Neurotransmitter switching is the gain of one neurotransmitter and the loss of another in the same neuron in response to chronic stimulation. Neurotransmitter receptors on postsynaptic cells change to match the identity of the newly expressed neurotransmitter. Neurotransmitter switching often appears to change the sign of the synapse from excitatory to inhibitory or from inhibitory to excitatory. In these cases, neurotransmitter switching and receptor matching thus change the polarity of the circuit in which they take place. Neurotransmitter switching produces up or down reversals of behavior. It is also observed in response to disease. These findings raise the possibility that neurotransmitter switching contributes to depression, schizophrenia, and other illnesses. Many early discoveries of the single gain or loss of a neurotransmitter may have been harbingers of neurotransmitter switching.


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Literature Cited

  1. Aimone JB, Li Y, Lee SW, Clemenson GD, Deng W, Gage FH. 2014. Regulation and function of adult neurogenesis: from genes to cognition. Physiol. Rev. 94:991–1026 [Google Scholar]
  2. Akbarian S, Kim JJ, Potkin SG, Hagman JO, Tafazzoli A. et al. 1995. Gene expression for glutamic acid decarboxylase is reduced without loss of neurons in prefrontal cortex of schizophrenics. Arch. Gen. Psychiatry 52:258–66 [Google Scholar]
  3. Apostolova G, Loy B, Dorn R, Dechant G. 2010. The sympathetic neurotransmitter switch depends on the nuclear matrix protein Satb2. J. Neurosci. 30:16356–64 [Google Scholar]
  4. Aumann TD, Gantois I, Egan K, Vais A, Tomas D. et al. 2008. SK channel function regulates the dopamine phenotype of neurons in the substantia nigra pars compacta. Exp. Neurol. 213:419–30 [Google Scholar]
  5. Aumann TD, Raabus M, Tomas D, Prijanto A, Churilov L. et al. 2016. Differences in number of midbrain dopamine neurons associated with summer and winter photoperiods in humans. PLOS ONE 11:e0158847 [Google Scholar]
  6. Aumann TD, Tomas D, Horne MK. 2013. Environmental and behavioral modulation of the number of substantia nigra dopamine neurons in adult mice. Brain Behav 3:617–25 [Google Scholar]
  7. Baker H. 1990. Unilateral, neonatal olfactory deprivation alters tyrosine hydroxylase expression but not aromatic amino acid decarboxylase or GABA immunoreactivity. Neuroscience 36:761–71 [Google Scholar]
  8. Baker H, Towle AC, Margolis FL. 1988. Differential afferent regulation of dopaminergic and GABAergic neurons in the mouse main olfactory bulb. Brain Res 450:69–80 [Google Scholar]
  9. Borodinsky LN, Root CM, Cronin JA, Sann SB, Gu X, Spitzer NC. 2004. Activity-dependent homeostatic specification of transmitter expression in embryonic neurons. Nature 429:523–30 [Google Scholar]
  10. Borodinsky LN, Spitzer NC. 2007. Activity-dependent neurotransmitter-receptor matching at the neuromuscular junction. PNAS 104:335–40 [Google Scholar]
  11. Brodski C, Schnürch H, Dechant G. 2000. Neurotrophin-3 promotes the cholinergic differentiation of sympathetic neurons. PNAS 97:9683–88 [Google Scholar]
  12. Brunelli G, Spano P, Barlati S, Guarneri B, Barbon A. et al. 2005. Glutamatergic reinnervation through peripheral nerve graft dictates assembly of glutamatergic synapses at rat skeletal muscle. PNAS 102:8752–57 [Google Scholar]
  13. Dal Bo G, Bérubé-Carrière N, Mendez JA, Leo D, Riad M. et al. 2008. Enhanced glutamatergic phenotype of mesencephalic dopamine neurons after neonatal 6-hydroxydopamine lesion. Neuroscience 156:59–70 [Google Scholar]
  14. Dela Cruz JAD, Hescham S, Adriaanse B, Campos FL, Steinbusch HWM. et al. 2014. Increased number of TH-immunoreactive cells in the ventral tegmental area after deep brain stimulation of the anterior nucleus of the thalamus. Brain Struct. Funct. 220:3061–66 [Google Scholar]
  15. Demarque M, Spitzer NC. 2010. Activity-dependent expression of Lmx1b regulates specification of serotonergic neurons modulating swimming behavior. Neuron 67:321–34 [Google Scholar]
  16. Dulcis D, Jamshidi P, Leutgeb S, Spitzer NC. 2013. Neurotransmitter switching in the adult brain regulates behavior. Science 340:449–53 [Google Scholar]
  17. Dulcis D, Spitzer NC. 2008. Illumination controls dopaminergic differentiation regulating behavior. Nature 456:195–201 [Google Scholar]
  18. Dunlop BW, Nemeroff CB. 2007. The role of dopamine in the pathophysiology of depression. Arch. Gen. Psychiatry 64:327–37 [Google Scholar]
  19. Ernsberger U. 2008. The role of GDNF family ligand signalling in the differentiation of sympathetic and dorsal root ganglion neurons. Cell Tissue Res 333:353–71 [Google Scholar]
  20. Francis NJ, Asmus SE, Landis SC. 1997. CNTF and LIF are not required for the target-directed acquisition of cholinergic and peptidergic properties by sympathetic neurons in vivo. Dev. Biol. 182:76–87 [Google Scholar]
  21. Francolini M, Brunelli G, Cambianica I, Barlati S, Barbon A. et al. 2009. Glutamatergic reinnervation and assembly of glutamatergic synapses in adult rat skeletal muscle occurs at cholinergic endplates. J. Neuropathol. Exp. Neurol. 68:1103–15 [Google Scholar]
  22. Fukada K. 1985. Purification and partial characterization of a cholinergic neuronal differentiation factor. PNAS 82:8795–99 [Google Scholar]
  23. Furshpan EJ, MacLeish PR, O'Lague PH, Potter DD. 1976. Chemical transmission between rat sympathetic neurons and cardiac myocytes developing in microcultures: evidence for cholinergic, adrenergic, and dual-function neurons. PNAS 73:4225–29 [Google Scholar]
  24. Godavarthi SK, Spitzer NC. 2016. Neurotransmitter switching in mouse prefrontal cortex. 2016 Neurosci. Meet. Plan., San Diego Program No. 36.04 San Diego, CA: Soc. Neurosci. [Google Scholar]
  25. Grant MP, Francis NJ, Landis SC. 1995. The role of acetylcholine in regulating secretory responsiveness in rat sweat glands. Mol. Cell. Neurosci. 6:32–42 [Google Scholar]
  26. Gu X, Olson EC, Spitzer NC. 1994. Spontaneous neuronal calcium spikes and waves during early differentiation. J. Neurosci. 14:6325–35 [Google Scholar]
  27. Gu X, Spitzer NC. 1995. Distinct aspects of neuronal differentiation encoded by frequency of spontaneous Ca2+ transients. Nature 375:784–87 [Google Scholar]
  28. Güemez-Gamboa A, Xu L, Meng D, Spitzer NC. 2014. Non-cell-autonomous mechanism of activity-dependent neurotransmitter switching. Neuron 82:1004–16 [Google Scholar]
  29. Gutierrez R. 2000. Seizures induce simultaneous GABAergic and glutamatergic transmission in the dentate gyrus-CA3 system. J. Neurophysiol. 84:3088–90 [Google Scholar]
  30. Gutierrez R. 2002. Activity-dependent expression of simultaneous glutamatergic and GABAergic neurotransmission from the mossy fibers in vitro. J. Neurophysiol. 87:2562–70 [Google Scholar]
  31. Habecker BA, Landis SC. 1994. Noradrenergic regulation of cholinergic differentiation. Science 264:1602–4 [Google Scholar]
  32. Habecker BA, Tresser SJ, Rao MS, Landis SC. 1995. Production of sweat gland cholinergic differentiation factor depends on innervation. Dev. Biol. 167:307–16 [Google Scholar]
  33. Hammond-Weinberger DR, Spitzer NC. 2015. Investigating intracellular signaling events involved in neurotransmitter-receptor matching. 2016 Neurosci. Meet. Plan., San Diego Program No. 30.07 San Diego, CA: Soc. Neurosci. [Google Scholar]
  34. Hendry SHC, Jones EG. 1986. Reduction in number of immunostained GABAergic neurones in deprived-eye dominance columns of monkey area 17. Nature 320:750–53 [Google Scholar]
  35. Hendry SHC, Jones EG. 1988. Activity-dependent regulation of GABA expression in the visual cortex of adult monkeys. Neuron 1:701–12 [Google Scholar]
  36. Higgins D, Iacovitti L, Joh TH, Burton H. 1981. The immunocytochemical localization of tyrosine hydroxylase within rat sympathetic neurons that release acetylcholine in culture. J. Neurosci. 1:126–31 [Google Scholar]
  37. Hnasko TS, Edwards RH. 2012. Neurotransmitter corelease: mechanism and physiological role. Annu. Rev. Physiol. 74:225–43 [Google Scholar]
  38. Holliday J, Spitzer NC. 1990. Spontaneous calcium influx and its roles in differentiation of spinal neurons in culture. Dev. Biol. 141:13–23 [Google Scholar]
  39. Huisman E, Uylings HB, Hoogland PV. 2004. A 100% increase of dopaminergic cells in the olfactory bulb may explain hyposmia in Parkinson's disease. Mov. Disord. 19:687–92 [Google Scholar]
  40. Iacovitti L, Joh TH, Park DH, Bunge RP. 1981. Dual expression of neurotransmitter synthesis in cultured autonomic neurons. J. Neurosci. 1:685–90 [Google Scholar]
  41. Kanazawa H, Ieda M, Kimura K, Arai T, Kawaguchi-Manabe H. et al. 2010. Heart failure causes cholinergic transdifferentiation of cardiac sympathetic nerves via gp130-signaling cytokines in rodents. J. Clin. Investig. 120:408–21 [Google Scholar]
  42. Korada S, Schwartz IR. 1999. Development of GABA, glycine, and their receptors in the auditory brainstem of gerbil: a light and electron microscopic study. J. Comp. Neurol. 409:664–81 [Google Scholar]
  43. Kosaka T, Kosaka K, Hama K, Wu JY, Nagatsu I. 1987. Differential effect of functional olfactory deprivation on the GABAergic and catecholaminergic traits in the rat main olfactory bulb. Brain Res 413:197–203 [Google Scholar]
  44. Kotak VC, Korada S, Schwartz IR, Sanes DH. 1998. A developmental shift from GABAergic to glycinergic transmission in the central auditory system. J. Neurosci. 18:4646–55 [Google Scholar]
  45. Lam RW, Levitt AJ, Levitan RD, Enns MW, Morehouse R. et al. 2006. The Can-SAD study: a randomized controlled trial of the effectiveness of light therapy and fluoxetine in patients with winter seasonal affective disorder. Am. J. Psych. 163:805–12 [Google Scholar]
  46. Landis SC. 1976. Rat sympathetic neurons and cardiac myocytes developing in microcultures: correlation of the fine structure of endings with neurotransmitter function in single neurons. PNAS 73:4220–24 [Google Scholar]
  47. Landis SC, Keefe D. 1983. Evidence for neurotransmitter plasticity in vivo: developmental changes in properties of cholinergic sympathetic neurons. Dev. Biol. 98:349–72 [Google Scholar]
  48. Le Douarin NM, Teillet M-A, Ziller C, Smith J. 1978. Adrenergic differentiation of cells of the cholinergic ciliary and Remak ganglia in avian embryo after in vivo transplantation. PNAS 75:2030–34 [Google Scholar]
  49. Li H, Jackson KB, Spitzer NC. 2016. Exercise-induced neurotransmitter switching in the adult mouse midbrain. 2016 Neurosci. Meet. Plan., San Diego Program No. 36.01 San Diego, CA: Soc. Neurosci. [Google Scholar]
  50. Loy B, Apostolova G, Dorn R, McGuire VA, Arthur JS, Dechant G. 2011. p38α and p38β mitogen-activated protein kinases determine cholinergic transdifferentiation of sympathetic neurons. J. Neurosci. 31:12059–67 [Google Scholar]
  51. Marek KW, Kurtz LM, Spitzer NC. 2010. cJun integrates calcium spike activity and tlx3 expression to regulate neurotransmitter specification. Nat. Neurosci. 13:944–50 [Google Scholar]
  52. Meng D, Leutgeb S, Deisseroth K, Spitzer NC. 2016. Neuronal activity regulates neurotransmitter switching in the adult brain. 2016 Neurosci. Meet. Plan., San Diego Program No. 36.03 San Diego, CA: Soc. Neurosci. [Google Scholar]
  53. Mundiñano IC, Caballero MC, Ordóñez C, Hernandez M, DiCaudo C. et al. 2011. Increased dopaminergic cells and protein aggregates in the olfactory bulb of patients with neurodegenerative disorders. Acta Neuropathol 122:61–74 [Google Scholar]
  54. Nabekura J, Katsurabayashi S, Kakazu Y, Shibata S, Matsubara A. et al. 2004. Developmental switch from GABA to glycine release in single central synaptic terminals. Nat. Neurosci. 7:17–23 [Google Scholar]
  55. Olivas A, Gardner RT, Wang L, Ripplinger CM, Woodward WR, Habecker BA. 2016. Myocardial infarction causes transient cholinergic transdifferentiation of cardiac sympathetic nerves via gp130. J. Neurosci. 36:479–88 [Google Scholar]
  56. Paquette V, Lévesque J, Mensour B, Leroux JM, Beaudoin G. et al. 2003. “Change the mind and you change the brain”: effects of cognitive-behavioral therapy on the neural correlates of spider phobia. NeuroImage 18:401–9 [Google Scholar]
  57. Patterson PH, Chun LLY. 1974. The influence of non-neuronal cells on catecholamine and acetylcholine synthesis and accumulation in cultures of dissociated sympathetic neurons. PNAS 71:3607–10 [Google Scholar]
  58. Patterson PH, Chun LLY. 1977. The induction of acetylcholine synthesis in primary cultures of dissociated rat sympathetic neurons. I. Effects of conditioned medium. Dev. Biol. 56:263–80 [Google Scholar]
  59. Patterson PH, Reichardt LF, Chun LLY. 1976. Biochemical studies on the development of primary sympathetic neurons in cell culture. Cold Spring Harb. Symp. Quant. Biol. 40:389–97 [Google Scholar]
  60. Pereira L, Kratsios P, Serrano-Saiz E, Sheftel H, Mayo AE. et al. 2015. A cellular and regulatory map of the cholinergic nervous system of C. elegans. eLife 4:e12432 [Google Scholar]
  61. Pierani A, Moran-Rivard L, Sunshine MJ, Littman DR, Goulding M, Jessell TM. 2001. Control of interneuron fate in the developing spinal cord by the progenitor homeodomain protein Dbx1. Neuron 29:367–84 [Google Scholar]
  62. Pillai A, Mansouri A, Behringer R, Westphal H, Goulding M. 2007. Lhx1 and Lhx5 maintain the inhibitory-neurotransmitter status of interneurons in the dorsal spinal cord. Development 134:357–66 [Google Scholar]
  63. Pocock R, Hobert O. 2010. Hypoxia activates a latent circuit for processing gustatory information in C. elegans. Nat. Neurosci. 13:610–14 [Google Scholar]
  64. Potter DD, Landis SC, Matsumoto SG, Furshpan EJ. 1986. Synaptic functions in rat sympathetic neurons in microcultures. II. Adrenergic/cholinergic dual status and plasticity. J. Neurosci. 6:1080–98 [Google Scholar]
  65. Rao MS, Landis SC, Patterson PH. 1990. The cholinergic neuronal differentiation factor from heart cell conditioned medium is different from the cholinergic factors in sciatic nerve and spinal cord. Dev. Biol. 139:65–74 [Google Scholar]
  66. Rao MS, Sun Y, Escary JL, Perreau J, Tresser S. et al. 1993. Leukemia inhibitory factor mediates an injury response but not a target-directed developmental transmitter switch in sympathetic neurons. Neuron 11:1175–85 [Google Scholar]
  67. Reichardt LF, Patterson PH. 1977. Neurotransmitter synthesis and uptake by isolated sympathetic neurones in microcultures. Nature 270:147–51 [Google Scholar]
  68. Romero PA, Shapiro MG, Arnold FH, Jasanoff A. 2013. Directed evolution of protein-based neurotransmitter sensors for MRI. Methods Mol. Biol. 995:193–205 [Google Scholar]
  69. Root CM, Velázquez-Ulloa NA, Monsalve GC, Minakova E, Spitzer NC. 2008. Embryonically expressed GABA and glutamate drive electrical activity regulating neurotransmitter specification. J. Neurosci. 28:4777–84 [Google Scholar]
  70. Saadat S, Sendtner M, Rohrer H. 1989. Ciliary neurotrophic factor induces cholinergic differentiation of rat sympathetic neurons in culture. J. Cell Biol. 108:1807–18 [Google Scholar]
  71. Schotzinger RJ, Landis SC. 1988. Cholinergic phenotype developed by noradrenergic sympathetic neurons after innervation of a novel cholinergic target in vivo. Nature 335:637–39 [Google Scholar]
  72. Schotzinger RJ, Landis SC. 1990. Acquisition of cholinergic and peptidergic properties by sympathetic innervation of rat sweat glands requires interaction with normal target. Neuron 5:91–100 [Google Scholar]
  73. Serrano-Saiz E, Poole RJ, Felton T, Zhang F, De La Cruz ED, Hobert O. 2013. Modular control of glutamatergic neuronal identity in C. elegans by distinct homeodomain proteins. Cell 155:659–73 [Google Scholar]
  74. Shabel SJ, Proulx CD, Piriz J, Malinow R. 2014. GABA/glutamate co-release controls habenula output and is modified by antidepressant treatment. Science 345:1494–98 [Google Scholar]
  75. Sillar KT, Reith CA, McDearmid JR. 1998. Development and aminergic neuromodulation of a spinal locomotor network controlling swimming in Xenopus larvae. Ann. N. Y. Acad. Sci. 860:318–32 [Google Scholar]
  76. Sperk G, Wieselthaler-Hölzl A, Pirker S, Tasan R, Strasser SS. et al. 2012. Glutamate decarboxylase 67 is expressed in hippocampal mossy fibers of temporal lobe epilepsy patients. Hippocampus 22:590–603 [Google Scholar]
  77. Spitzer NC. 1985. The control of development of neuronal excitability. Molecular Bases of Neural Development GM Edelman, WE Gall, WM Cowan 67–88 New York: Rockefeller Univ. Press [Google Scholar]
  78. Spitzer NC, de Baca RC, Allen KA, Holliday J. 1993. Calcium dependence of differentiation of GABA immunoreactivity in spinal neurons. J. Comp. Neurol. 337:168–75 [Google Scholar]
  79. Spitzer NC, Lamborghini JE. 1976. The development of the action potential mechanism of amphibian neurons isolated in culture. PNAS 73:1641–45 [Google Scholar]
  80. Stanke M, Duong CV, Pape M, Geissen M, Burbach G. et al. 2006. Target-dependent specification of the neurotransmitter phenotype: cholinergic differentiation of sympathetic neurons is mediated in vivo by gp130 signaling. Development 133:141–50 [Google Scholar]
  81. Straub J, Plener PL, Sproeber N, Sprenger L, Koelch MG. et al. 2015. Neural correlates of successful psychotherapy of depression in adolescents. J. Affect. Disord. 183:239–46 [Google Scholar]
  82. Tanabe Y, William C, Jessell TM. 1998. Specification of motor neuron identity by the MNR2 homeodomain protein. Cell 95:67–80 [Google Scholar]
  83. Tandé D, Hoglinger G, Debeir T, Freundlieb N, Hirsch EC, Francois C. 2006. New striatal dopamine neurons in MPTP-treated macaques result from a phenotypic shift and not neurogenesis. Brain 129:1194–200 [Google Scholar]
  84. Thor S, Thomas JB. 1997. The Drosophila islet gene governs axon pathfinding and neurotransmitter identity. Neuron 18:397–409 [Google Scholar]
  85. Tritsch NX, Granger AJ, Sabatini BL. 2016. Mechanisms and functions of GABA co-release. Nat. Rev. Neurosci. 17:139–45 [Google Scholar]
  86. Vaaga CE, Borisovska M, Westbrook GL. 2014. Dual-transmitter neurons: functional implications of co-release and co-transmission. Curr. Opin. Neurobiol. 29:25–32 [Google Scholar]
  87. Waldman B. 1981. Sibling recognition in toad tadpoles: the role of experience. Z. Tierpsychol. 56:341–58 [Google Scholar]
  88. Waldman B. 1985. Olfactory basis of kin recognition in toad tadpoles. J. Comp. Physiol. A Sens. Neural Behav. Physiol. 156:565–77 [Google Scholar]
  89. Walicke PA, Campenot RB, Patterson PH. 1977. Determination of transmitter function by neuronal activity. PNAS 74:5767–71 [Google Scholar]
  90. Walicke PA, Patterson PH. 1981. On the role of Ca2+ in the transmitter choice made by cultured sympathetic neurons. J. Neurosci. 4:343–50 [Google Scholar]
  91. Watt SD, Gu X, Smith RD, Spitzer NC. 2000. Specific frequencies of spontaneous Ca2+ transients upregulate GAD 67 transcripts in embryonic neurons. Mol. Cell. Neurosci. 16:376–87 [Google Scholar]
  92. Wolinsky E, Patterson PH. 1983. Tyrosine hydroxylase activity decreases with induction of cholinergic properties in cultured sympathetic neurons. J. Neurosci. 3:1495–500 [Google Scholar]
  93. Yamamori T, Fukada K, Aebersold R, Korsching S, Fann M-J, Patterson PH. 1989. The cholinergic neuronal differentiation factor from heart cells is identical to leukemia inhibitory factor. Science 246:1412–16 [Google Scholar]
  94. Yoshimura S, Okamoto Y, Onoda K, Matsunaga M, Okada G. et al. 2014. Cognitive behavioral therapy for depression changes medial prefrontal and ventral anterior cingulate cortex activity associated with self-referential processing. Soc. Cogn. Affect. Neurosci. 9:487–93 [Google Scholar]
  95. Zambetti S, Connors JO, Spitzer NC. 2016. Neurotransmitter switching in the adult mammalian hippocampus. 2016 Neurosci. Meet. Plan., San Diego Program No. 36.02 San Diego, CA: Soc. Neurosci. [Google Scholar]

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