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Activity-dependent neurotransmitter respecification

Nature Reviews Neuroscience volume 13, pages 94–106 (2012)Cite this article

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Key Points

  • The transmitters expressed by neurons have been thought to be a constant and immutable aspect of neuronal identity, but recent work shows that electrical activity can respecify transmitter expression in both the developing and the mature nervous system.

  • This process seems to promote homeostatic equilibrium of excitability by changing the transmitters neurons synthesize and release, suggesting that this equilibrium is important for normal maturation of the nervous system and maintenance of homeostasis in circuits. Perturbations of embryonic activity with drugs may alter the composition and function of the nervous system by disturbing crucial homeostatic regulation of excitability.

  • Transmitter respecification involves induction of transmitter expression in reserve pool neurons that already express other transmitters and are wired into circuits. Activity reprograms these neurons to express an additional transmitter or switch from one transmitter to another.

  • At the molecular level, activity engages the expression of transcription factors that alter the expression of genes encoding enzymes involved in neurotransmitter synthesis and transmitter transporters that drive transmitter respecification.

  • Activity-dependent changes in transmitter specification are matched by corresponding changes in the expression of the cognate postsynaptic receptors, enabling synaptic transmission by the novel transmitters.

  • Neurons expressing a new neurotransmitter can drive appropriate behaviours at early stages of development, putting activity-dependent transmitter specification on a functional map. Given that the structure and function of the nervous system track changes in the environment, it seems likely that activity-dependent changes in transmitter identity are a mechanism that enables behaviour to change flexibly.

  • Pathological loss of neurotransmitters and their receptors may be treated therapeutically by sensorimotor stimulation that drives transmitter respecification and hijacks existing neuronal circuitry.

Abstract

For many years it has been assumed that the identity of the transmitters expressed by neurons is stable and unchanging. Recent work, however, shows that electrical activity can respecify neurotransmitter expression during development and in the mature nervous system, and an understanding is emerging of the molecular mechanisms underlying activity-dependent transmitter respecification. Changes in postsynaptic neurotransmitter receptor expression accompany and match changes in transmitter specification, thus enabling synaptic transmission. The functional roles of neurotransmitter respecification are beginning to be understood and appear to involve homeostatic synaptic regulation, which in turn influences behaviour. Activation of this novel form of plasticity by sensorimotor stimuli may provide clinical benefits.

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Figure 1: Developmental context for activity-dependent neurotransmitter respecification.
Figure 2: Activity-dependent transmitter respecification in neurons distinguished by molecular markers of neuronal identity in the developing Xenopus laevis spinal cord and hypothalamus.
Figure 3: Molecular mechanisms of activity-dependent transmitter respecification in the Xenopus laevis CNS.
Figure 4: Transmitter receptor expression matches activity-dependent transmitter respecification in Xenopus laevis larvae.
Figure 5: Activity-dependent changes in transmitter expression regulate behaviours in Xenopus laevis larvae.

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References

  1. Spitzer, N. C. & Lamborghini, J. E. The development of the action potential mechanism of amphibian neurons isolated in culture. Proc. Natl Acad. Sci. USA 73, 1641–1645 (1976).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Spitzer, N. C., Debaca, R. C., Allen, K. A. & Holliday, J. Calcium dependence of differentiation of GABA immunoreactivity in spinal neurons. J. Comp. Neurol. 337, 168–175 (1993).

    Article  CAS  PubMed  Google Scholar 

  3. Baccaglini, P. I. & Spitzer, N. C. Developmental changes in the inward current of the action potential of Rohon-Beard neurones. J. Physiol. 271, 93–117 (1977).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Roberts, A., Dale, N., Ottersen, O. P. & Storm-Mathisen, J. The early development of neurons with GABA immunoreactivity in the CNS of Xenopus laevis embryos. J. Comp. Neurol. 261, 435–449 (1987).

    Article  CAS  PubMed  Google Scholar 

  5. Dale, N., Roberts, A., Ottersen, O. P. & Storm-Mathisen, J. The development of a population of spinal cord neurons and their axonal projections revealed by GABA immunocytochemistry in frog embryos. Proc. R. Soc. Lond. B 232, 205–215 (1987).

    Article  CAS  PubMed  Google Scholar 

  6. Root, C. M. et al. Embryonically expressed GABA and glutamate drive electrical activity regulating neurotransmitter specification. J. Neurosci. 28, 4777–4784 (2008). This study identified paracrine actions of GABA and glutamate as triggers for spontaneous calcium spikes that regulate neurotransmitter respecification.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Gu, X. & Spitzer, N. C. Distinct aspects of neuronal differentiation encoded by frequency of spontaneous Ca2+ transients. Nature 375, 784–787 (1995). This paper provided the first demonstration of coding of neuronal differentiation by low-frequency, long-duration calcium transients.

    Article  CAS  PubMed  Google Scholar 

  8. Watt, S. D., Gu, X., Smith, R. D. & Spitzer N.C. Specific frequencies of spontaneous Ca2+ transients upregulate GAD 67 transcripts in embryonic spinal neurons. Mol. Cell. Neurosci. 16, 376–387 (2000).

    Article  CAS  PubMed  Google Scholar 

  9. Borodinsky, L. N. et al. Activity-dependent homeostatic specification of transmitter expression in embryonic neurons. Nature 429, 523–530 (2004). This study demonstrated homeostatic neurotransmitter respecification in the developing vertebrate spinal cord in the absence of changes in molecular markers of cell identity.

    Article  CAS  PubMed  Google Scholar 

  10. Turrigiano, G. G. The self-tuning neuron: synaptic scaling of excitatory synapses. Cell 135, 422–435 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Davis, G. W. Homeostatic control of neural activity: from phenomenology to molecular design. Ann. Rev. Neurosci. 29, 307–323 (2006).

    Article  CAS  PubMed  Google Scholar 

  12. Marder, E. Quantification of Behavior Sackler Colloquium: variability, compensation, and modulation in neurons and circuits. Proc. Natl Acad. Sci. USA 108 (Suppl. 3), 15542–15548 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Demarque, M. & Spitzer, N. C. Activity-dependent expression of Lmx1b regulates specification of serotonergic neurons modulating swimming behavior. Neuron 67, 321–334 (2010). This study identified a molecular mechanism by which activity regulates neurotransmitter respecification and revealed the behavioural impact of new neurotransmitter expression.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Dulcis, D. & Spitzer, N. C. Illumination controls dopaminergic differentiation regulating behavior. Nature 456, 195–201 (2008). This paper demonstrated that sensory input respecifies neurotransmitter expression and the expression of the cognate postsynaptic neurotransmitter receptors that enable camouflage behaviour.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Velázquez-Ulloa, N. A., Spitzer, N. C. & Dulcis, D. Contexts for dopamine specification by calcium spike activity in the CNS. J. Neurosci. 31, 78–88 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Baker, H. Unilateral, neonatal olfactory deprivation alters tyrosine hydroxylase expression but not aromatic amino acid decarboxylase or GABA immunoreactivity. Neuroscience 36, 761–771 (1990).

    Article  CAS  PubMed  Google Scholar 

  17. Dulcis, D. & Spitzer, N. C. Reserve pool neuron transmitter respecification: novel neuroplasticity. Dev. Neurobiol. 18 May 2011 (doi:10.1002/dneu.20920).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Ben-Ari, Y. & Spitzer, N. C. Phenotypic checkpoints regulate neuronal development. Trends Neurosci. 33, 485–492 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Hökfelt, T. et al. Occurrence of somatostatin-like immunoreactivity in some peripheral sympathetic noradrenergic neurons. Proc. Natl Acad. Sci. USA 74, 3587–3591 (1977).

    Article  PubMed  PubMed Central  Google Scholar 

  20. Hökfelt, T. et al. Peptidergic neurones. Nature 284, 515–521 (1980).

    Article  PubMed  Google Scholar 

  21. Furshpan, E. J., MacLeish, P. R., O'Lague, P. H. & Potter, D. D. Chemical transmission between rat sympathetic neurons and cardiac myocytes developing in microcultures: evidence for cholinergic, adrenergic, and dual-function neurons. Proc. Natl Acad. Sci. USA 73, 4225–4229 (1976).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Potter, D. D., Landis, S. C. & Furshpan, E. J. Dual function during development of rat sympathetic neurones in culture. J. Exp. Biol. 89, 57–71 (1980).

    CAS  PubMed  Google Scholar 

  23. Demarque, M. & Spitzer, N. C. Neurotransmitter phenotype plasticity: an unexpected mechanism in the toolbox of network activity homeostasis. Dev. Neurobiol. 72, 22–32 (2011).

    Article  CAS  Google Scholar 

  24. Nishimaru, H. et al. Mammalian motor neurons corelease glutamate and acetylcholine at central synapses. Proc. Natl Acad. Sci. USA 102, 5245–5249 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Mentis, G. Z. et al. Noncholinergic excitatory actions of motoneurons in the neonatal mammalian spinal cord. Proc. Natl Acad. Sci. USA 102, 7344–7349 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Soussi, R. et al. Heterogeneity of the supramammillary-hippocampal pathways: evidence for a unique GABAergic neurotransmitter phenotype and regional differences. Eur. J. Neurosci. 32, 771–785 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  27. Gras, C. et al. A third vesicular glutamate transporter expressed by cholinergic and serotoninergic neurons. J. Neurosci. 22, 5442–5451 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Amilhon, B. et al. VGLUT3 (vesicular glutamate transporter type 3) contribution to the regulation of serotonergic transmission and anxiety. J. Neurosci. 30, 2198–2210 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Seal, R. P. & Edwards, R. H. Functional implications of neurotransmitter co-release: glutamate and GABA share the load. Curr. Opin. Pharmacol. 6, 114–119 (2006).

    Article  CAS  PubMed  Google Scholar 

  30. Chang, L. W. & Spitzer, N. C. Spontaneous calcium spike activity in embryonic spinal neurons is regulated by developmental expression of the Na+, K+-ATPase β3 subunit. J. Neurosci. 29, 7877–7885 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. McCabe, A. K., Chisholm, S. L., Picken-Bahrey, H. L. & Moody, W. J. The self-regulating nature of spontaneous synchronized activity in developing mouse cortical neurones. J. Physiol. 577, 155–167 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Echelard, Y. et al. Sonic hedgehog, a member of a family of putative signaling molecules, is implicated in the regulation of CNS polarity. Cell 75, 1417–1430 (1993).

    Article  CAS  PubMed  Google Scholar 

  33. Roelink, H. et al. Floor plate and motor neuron induction by different concentrations of the amino-terminal cleavage product of sonic hedgehog autoproteolysis. Cell 81, 445–455 (1995).

    Article  CAS  PubMed  Google Scholar 

  34. Ericson, J. et al. Two critical periods of Sonic Hedgehog signaling required for the specification of motor neuron identity. Cell 87, 661–673 (1996).

    Article  CAS  PubMed  Google Scholar 

  35. Belgacem, Y. H. & Borodinsky, L. N. Sonic hedgehog signaling is decoded by calcium spike activity in the developing spinal cord. Proc. Natl Acad. Sci. USA 108, 4482–4487 (2011). This study shows that the concentration of the morphogen SHH controls the frequency of calcium spikes that regulate neurotransmitter respecification.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. De Koninck, P. & Schulman, H. Sensitivity of CaM kinase II to the frequency of Ca2+ oscillations. Science 279, 227–230 (1998).

    Article  CAS  PubMed  Google Scholar 

  37. Oancea, E. & Meyer, T. Protein kinase C as a molecular machine for decoding calcium and diacylglycerol signals. Cell 95, 307–318 (1996).

    Article  Google Scholar 

  38. Eshete, F. & Fields, R. D. Spike frequency decoding and autonomous activation of Ca2+-calmodulin-dependent protein kinase II in dorsal root ganglion neurons. J. Neurosci. 21, 6694–6705 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Brosenitsch, T. A., Salgado-Commissariat, D., Kunze, D. L. & Katz, D. M. A role for L-type calcium channels in developmental regulation of transmitter phenotype in primary sensory neurons. J. Neurosci. 18, 1047–1055 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Brosenitsch, T. A. & Katz, D. M. Physiological patterns of electrical stimulation can induce neuronal gene expression by activating N-type calcium channels. J. Neurosci. 21, 2571–2579 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Chevalier, J. et al. Activity-dependent regulation of tyrosine hydroxylase expression in the enteric nervous system. J. Physiol. 586, 1963–1975 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Belousov, A. B., O'Hara, B. F. & Denisova, J. V. Acetylcholine becomes the major excitatory neurotransmitter in the hypothalamus in vitro in the absence of glutamate excitation. J. Neurosci. 21, 2015–2027 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Belousov, A. B., Hunt, N. D., Raju, R. P. & Denisova, J. V. Calcium-dependent regulation of cholinergic cell phenotype in the hypothalamus in vitro. J. Neurophysiol. 88, 1352–1362 (2002).

    Article  CAS  PubMed  Google Scholar 

  44. Liu, X. et al. Regulation of cholinergic phenotype in developing neurons. J. Neurophysiol. 99, 2443–2455 (2008). This paper demonstrated respecification of choline acetyltransferase expression in hypothalamic neurons following blockade or inactivation of NMDA receptors.

    Article  CAS  PubMed  Google Scholar 

  45. Thor, S. & Thomas, J. B. The Drosophila islet gene governs axon pathfinding and neurotransmitter identity. Neuron 18, 397–409 (1997).

    Article  CAS  PubMed  Google Scholar 

  46. Pierani, A. et al. Control of interneuron fate in the developing spinal cord by the progenitor homeodomain protein Dbx1. Neuron 29, 367–384 (2001).

    Article  CAS  PubMed  Google Scholar 

  47. Tanabe, Y., William, C. & Jessell, T. M. Specification of motor neuron identity by the MNR2 homeodomain protein. Cell 95, 67–80 (1998).

    Article  CAS  PubMed  Google Scholar 

  48. Roybon, L. et al. GABAergic differentiation induced by Mash1 is compromised by the bHLH proteins Neurogenin2, NeuroD1, and NeuroD2. Cereb. Cortex 20, 1234–1244 (2010).

    Article  PubMed  Google Scholar 

  49. Brosenitsch, T. A. & Katz, D. M. Expression of Phox2 transcription factors and induction of the dopaminergic phenotype in primary sensory neurons. Mol. Cell. Neurosci. 20, 447–457 (2002). This study showed that temporal and spatial expression of PHOX2 transcription factors is correlated with the potential for activity-dependent induction of the dopaminergic phenotype.

    Article  CAS  PubMed  Google Scholar 

  50. Cheng, L. et al. Tlx3 and Tlx1 are post-mitotic selector genes determining glutamatergic over GABAergic cell fates. Nature Neurosci. 7, 510–517 (2004).

    Article  CAS  PubMed  Google Scholar 

  51. Cheng, L. et al. Lbx1 and Tlx3 are opposing switches in determining GABAergic versus glutamatergic transmitter phenotypes. Nature Neurosci. 8, 1510–1515 (2005).

    Article  CAS  PubMed  Google Scholar 

  52. Marek, K. W., Kurtz, L. M. & Spitzer, N. C. cJun integrates calcium spike activity and tlx3 expression to regulate neurotransmitter specification. Nature Neurosci. 13, 944–950 (2010). This study identified a molecular mechanism for activity-dependent neurotransmitter respecification involving phosphorylation of c-Jun and its binding to a CRE site in the promoter of the glutamate/GABA selector gene tlx3.

    Article  CAS  PubMed  Google Scholar 

  53. Flames, N. & Hobert, O. Gene regulatory logic of dopamine neuron differentiation. Nature 458, 885–889 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Borodinsky, L. N. & Spitzer, N. C. Activity-dependent neurotransmitter-receptor matching at the neuromuscular junction. Proc. Natl Acad. Sci. USA 104, 335–340 (2007). This paper demonstrated the presence of non-cholinergic postsynaptic currents following activity-dependent neurotransmitter respecification in the embryonic spinal cord.

    Article  CAS  PubMed  Google Scholar 

  55. Marrus, S. B. & DiAntonio, A. Preferential localization of glutamate receptors opposite sites of high presynaptic release. Curr. Biol. 14, 924–931 (2004).

    Article  CAS  PubMed  Google Scholar 

  56. Kummer, T. T., Misgeld, T. & Sanes, J. R. Assembly of the postsynaptic membrane at the neuromuscular junction: paradigm lost. Curr. Opin. Neurobiol. 16, 74–82 (2006).

    Article  CAS  PubMed  Google Scholar 

  57. Cesa, R., Morando, L. & Strata, P. Transmitter-receptor mismatch in GABAergic synapses in the absence of activity. Proc. Natl Acad. Sci. USA 105, 18988–18993 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Catalano, S. M., Chang, C. K. & Shatz, C. J. Activity-dependent regulation of NMDAR1 immunoreactivity in the developing visual cortex. J. Neurosci. 17, 8376–8390 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Gu, Q. et al. Effects of tetrodotoxin treatment in LGN on neuromodulatory receptor expression in developing visual cortex. Brain Res. Dev. Brain Res. 106, 93–99 (1998).

    Article  CAS  PubMed  Google Scholar 

  60. Shi, J., Townsend, M. & Constantine-Paton, M. Activity-dependent induction of tonic calcineurin activity mediates a rapid developmental downregulation of NMDA receptor currents. Neuron 28, 103–114 (2000).

    Article  CAS  PubMed  Google Scholar 

  61. Sillar, K. T., Reith, C. A. & McDearmid, J. R. Development and aminergic neuromodulation of a spinal locomotor network controlling swimming in Xenopus larvae. Ann. NY Acad. Sci. 860, 318–332 (1998).

    Article  CAS  PubMed  Google Scholar 

  62. Kosaka, T. et al. Differential effect of functional olfactory deprivation on the GABAergic and catecholaminergic traits in the rat main olfactory bulb. Brain Res. 413, 197–203 (1987).

    Article  CAS  PubMed  Google Scholar 

  63. Baker, H., Morel, K., Stone, D. M. & Maruniak, J. A. Adult naris closure profoundly reduces tyrosine hydroxylase expression in mouse olfactory bulb. Brain Res. 614, 109–116 (1993).

    Article  CAS  PubMed  Google Scholar 

  64. Tu, S., Butt, C. M., Pauly, J. R. & Debski, E. A. Activity-dependent regulation of substance P expression and topographic map maintenance by a cholinergic pathway. J. Neurosci. 20, 5346–5357 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Gutiérrez, R. Seizures induce simultaneous GABAergic and glutamatergic transmission in the dentate gyrus-CA3 system. J. Neurophysiol. 84, 3088–3090 (2000).

    Article  PubMed  Google Scholar 

  66. Gutiérrez, R. Activity-dependent expression of simultaneous glutamatergic and GABAergic neurotransmission from the mossy fibers in vitro. J. Neurophysiol. 87, 2562–2570 (2002). This study demonstrated activity-dependent neurotransmitter switching in the adult rat brain.

    Article  PubMed  Google Scholar 

  67. Gutiérrez, R. et al. Plasticity of the GABAergic phenotype of the “glutamatergic” granule cells of the rat dentate gyrus. J. Neurosci. 23, 5594–5598 (2003).

    Article  PubMed  PubMed Central  Google Scholar 

  68. Uchigashima, M. et al. Evidence against GABA release from glutamatergic mossy fiber terminals in the developing hippocampus, J. Neurosci. 27, 8088–8100 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Hendry, S. H. & Jones, E. G. Reduction in number of immunostained GABAergic neurones in deprived-eye dominance columns of monkey area 17. Nature 320, 750–753 (1986). This paper revealed activity-dependent neurotransmitter respecification in the adult primate brain.

    Article  CAS  PubMed  Google Scholar 

  70. Hendry, S. H. & Jones, E. G. Activity-dependent regulation of GABA expression in the visual cortex of adult monkeys. Neuron 1, 701–712 (1988).

    Article  CAS  PubMed  Google Scholar 

  71. Perlstein, W. M., Carter, C. S., Noll, D. C. & Cohen, J. D. Relation of prefrontal cortex dysfunction to working memory and symptoms in schizophrenia. Am. J. Psychiatry 158, 1105–1113 (2001).

    Article  CAS  PubMed  Google Scholar 

  72. Akbarian, S. et al. Gene expression for glutamic acid decarboxylase is reduced without loss of neurons in prefrontal cortex of schizophrenics. Arch. Gen. Psychiatry 52, 258–266 (1995).

    Article  CAS  PubMed  Google Scholar 

  73. Brunelli, G. et al. Glutamatergic reinnervation through peripheral nerve graft dictates assembly of glutamatergic synapses at rat skeletal muscle. Proc. Natl Acad. Sci. USA 102, 8752–8757 (2005). This study illustrated the plasticity of neurotransmitter receptor expression at the adult mammalian neuromuscular junction.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Hirsch, E., Graybiel, A. M. & Agid, Y. A. Melanized dopaminergic neurons are differentially susceptible to degeneration in Parkinson's disease. Nature 334, 345–348 (1988).

    Article  CAS  PubMed  Google Scholar 

  75. Hartmann, A. et al. Caspase-3: a vulnerability factor and final effector in apoptotic death of dopaminergic neurons in Parkinson's disease. Proc. Natl Acad. Sci. USA 97, 2875–2880 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Whitehouse, P. J. et al. Alzheimer disease: evidence for selective loss of cholinergic neurons in the nucleus basalis. Ann. Neurol. 10, 122–126 (1981).

    Article  CAS  PubMed  Google Scholar 

  77. Kar, S., Slowikowski, S. P., Westaway, D. & Mount, H. T. Interactions between beta-amyloid and central cholinergic neurons: implications for Alzheimer's disease. J. Psychiatry Neurosci. 29, 427–441 (2004).

    PubMed  PubMed Central  Google Scholar 

  78. Muddashetty, R. S. et al. Dysregulated metabotropic glutamate receptor-dependent translation of AMPA receptor and postsynaptic density-95 mRNAs at synapses in a mouse model of fragile X syndrome. J. Neurosci. 27, 5338–5348 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Nakamoto, M. et al. Fragile X mental retardation protein deficiency leads to excessive mGluR5-dependent internalization of AMPA receptors. Proc. Natl Acad. Sci. USA 104, 15537–15542 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Lam, R. W. & Levitan, R. D. Pathophysiology of seasonal affective disorder: a review. J. Psychiatry Neurosci. 25, 469–480 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Lam, R. W. et al. 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. Psychiatry 163, 805–812 (2006).

    Article  PubMed  Google Scholar 

  82. Trevino, M. & Gutierrez, R. The GABAergic projection of the dentate gyrus to hippocampal area CA3 of the rat: pre- and postsynaptic actions after seizures. J. Physiol. 567, 939–949 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Trevino, M., Vivar, C. & Gutierrez, R. β/γ oscillatory activity in the CA3 hippocampal area is depressed by aberrant GABAergic transmission from the dentate gyrus after seizures. J. Neurosci. 27, 251–259 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Tandé, D. et al. New striatal dopamine neurons in MPTP-treated macaques result from a phenotypic shift and not neurogenesis. Brain 129, 1194–1200 (2006).

    Article  PubMed  Google Scholar 

  85. Aumann, T. D. et al. SK channel function regulates the dopamine phenotype of neurons in the substantia nigra pars compacta. Exp. Neurol. 213, 419–430 (2008).

    Article  CAS  PubMed  Google Scholar 

  86. Patt, S., Gertz, H. J., Gerhard, L. & Cervós-Navarro, J. Pathological changes in dendrites of substantia nigra neurons in Parkinson's disease: a Golgi study. Histol. Histopathol. 6, 373–380 (1991).

    CAS  PubMed  Google Scholar 

  87. Gerfen, C. R. The neostriatal mosaic: compartmentalization of corticostriatal input and striatonigral output systems. Nature 311, 461–464 (1984).

    Article  CAS  PubMed  Google Scholar 

  88. Gerfen, C. R., Herkenham, M. & Thibault, J. The neostriatal mosaic: II. Patch- and matrix-directed mesostriatal dopaminergic and non-dopaminergic systems. J. Neurosci. 7, 3915–3934 (1987).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Hontanilla B, de las Heras, S. & Giménez-Amaya, J. M. A topographic re-evaluation of the nigrostriatal projections to the caudate nucleus in the cat with multiple retrograde tracers. Neuroscience 72, 485–503 (1996).

    Article  CAS  PubMed  Google Scholar 

  90. Rodríguez, M. & González-Hernández, T. Electrophysiological and morphological evidence for a GABAergic nigrostriatal pathway. J. Neurosci. 19, 4682–4694 (1999).

    Article  PubMed  PubMed Central  Google Scholar 

  91. Earhart, G. M. Dance as therapy for individuals with Parkinson disease. Eur. J. Phys. Rehabil. Med. 45, 231–238 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Mendez, J. A. et al. Developmental and target-dependent regulation of vesicular glutamate transporter expression by dopamine neurons. J. Neurosci. 28, 6309–6318 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Dal Bo, G. et al. Enhanced glutamatergic phenotype of mesencephalic dopamine neurons after neonatal 6-hydroxydopamine lesion. Neuroscience 156, 59–70 (2008).

    Article  CAS  PubMed  Google Scholar 

  94. O'Dowd, D. K., Ribera, A. B. & Spitzer, N. C. Development of voltage-dependent calcium, sodium, and potassium currents in Xenopus spinal neurons. J. Neurosci. 18, 792–805 (1988).

    Article  Google Scholar 

  95. Lockery, S. R. & Spitzer, N. C. Reconstruction of action potential development from whole-cell currents of differentiating spinal neurons. J. Neurosci. 12, 2268–2287 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. McCobb, D. P., Best, P. M. & Beam, K. G. The differentiation of excitability in embryonic chick limb motoneurons. J. Neurosci. 10, 2974–2984 (1990).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Baines, R. A. & Bate, M. Electrophysiological development of central neurons in the Drosophila embryo. J. Neurosci. 18, 4673–4683 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Corlew, R., Bosma, M. M. & Moody, W. J. Spontaneous, synchronous electrical activity in neonatal mouse cortical neurones. J. Physiol. 560, 377–390 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Moreno, R. L. & Ribera, A. B. Zebrafish motor neuron subtypes differ electrically prior to axonal outgrowth. J. Neurophysiol. 102, 2477–2484 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  100. Espósito, M. S. et al. Neuronal differentiation in the adult hippocampus recapitulates embryonic development. J. Neurosci. 25, 10074–10086 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Bixby, J. L. & Spitzer, N. C. Early differentiation of vertebrate spinal neurons in the absence of voltage-dependent Ca2+ and Na+ influx. Dev. Biol. 106, 89–96 (1984).

    Article  CAS  PubMed  Google Scholar 

  102. Henderson, L. P., Smith, M. A. & Spitzer, N. C. The absence of calcium blocks impulse-evoked release of acetylcholine but not de novo formation of functional neuromuscular synaptic contacts in culture. J. Neurosci. 4, 3140–3150 (1984).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Holliday, J. & Spitzer, N. C. Spontaneous calcium influx and its roles in differentiation of spinal neurons in culture. Dev. Biol. 141, 13–23 (1990).

    Article  CAS  PubMed  Google Scholar 

  104. Gu, X. & Spitzer, N. C. Low-threshold Ca2+ current and its role in spontaneous elevations of intracellular Ca2+ in developing Xenopus neurons. J. Neurosci. 13, 4936–4948 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Gu, X., Olson, E. C. & Spitzer, N. C. Spontaneous neuronal calcium spikes and waves during early differentiation. J. Neurosci. 14, 6325–6335 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Walicke, P. A., Campenot, R. B. & Patterson, P. H. Determination of transmitter function by neuronal activity. Proc. Natl Acad. Sci. USA 74, 5767–5771 (1977).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Sun, Y. A. & Poo, M. M. Evoked release of acetylcholine from the growing embryonic neuron. Proc. Natl Acad. Sci. USA 84, 2540–2544 (1987).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Hartenstein, V. Early pattern of neuronal differentiation in the Xenopus embryonic brainstem and spinal cord. J. Comp. Neurol. 328, 213–231 (1993).

    Article  CAS  PubMed  Google Scholar 

  109. Spitzer, N. C. & Borodinsky, L. N. Implications of activity-dependent neurotransmitter-receptor matching. Phil. Trans. R. Soc. B 363, 1393–1399 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

I thank L. Borodinsky, D. Dulcis and M. Demarque for their comments and suggestions for the manuscript. N.C.S. is supported by grants NS15918 and NS57690 from the US National Institutes of Health.

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  1. Division of Biological Sciences, Neurobiology Section, Kavli Institute for Brain and Mind, University of California at San Diego, La Jolla, 92093, California, USA

    Nicholas C. Spitzer

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Glossary

Activity-dependent neurotransmitter respecification

Expression or loss of a transmitter or switch between expression of one transmitter and another in response to changes in activity.

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Spitzer, N. Activity-dependent neurotransmitter respecification. Nat Rev Neurosci 13, 94–106 (2012). https://doi.org/10.1038/nrn3154

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