Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Mechanisms underlying spontaneous patterned activity in developing neural circuits

Nature Reviews Neuroscience volume 11, pages 18–29 (2010)Cite this article

Key Points

  • During development, several different circuits of the CNS spontaneously generate correlated firing patterns that are distinct from activity patterns observed in the mature state.

  • The spontaneously active circuits described here are the spinal cord, cochlea, retina, hippocampus and cerebellum.

  • Although spontaneously active circuits have unique architectures, they use similar strategies to generate activity.

  • One of the common features is the existence of transient excitatory networks, consisting of depolarizing GABA (γ-aminobutyric acid), transient synaptic connections or gap junction coupling.

  • Another common feature is the presence of pacemaker-like neurons that are involved in the spontaneous generation of events.

  • There are many examples in which the absence of a crucial network component leads to the generation of spontaneous correlated activity by a compensatory circuit. This indicates that a given region of the CNS can use multiple strategies to generate spontaneous activity.

Abstract

Patterned, spontaneous activity occurs in many developing neural circuits, including the retina, the cochlea, the spinal cord, the cerebellum and the hippocampus, where it provides signals that are important for the development of neurons and their connections. Despite there being differences in adult architecture and output across these various circuits, the patterns of spontaneous network activity and the mechanisms that generate it are remarkably similar. The mechanisms can include a depolarizing action of GABA (γ-aminobutyric acid), transient synaptic connections, extrasynaptic transmission, gap junction coupling and the presence of pacemaker-like neurons. Interestingly, spontaneous activity is robust; if one element of a circuit is disrupted another will generate similar activity. This research suggests that developing neural circuits exhibit transient and tunable features that maintain a source of correlated activity during crucial stages of development.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Homeostatic regulation of spontaneous network activity in the chick spinal cord.
Figure 2: Homeostatic regulation of spontaneous network activity in the mammalian retina.

Similar content being viewed by others

References

  1. Owens, D. F. & Kriegstein, A. R. Is there more to GABA than synaptic inhibition? Nature Rev. Neurosci. 3, 715–727 (2002).

    Article  CAS  Google Scholar 

  2. Spitzer, N. C. Electrical activity in early neuronal development. Nature 444, 707–712 (2006).

    Article  CAS  PubMed  Google Scholar 

  3. Galli, L. & Maffei, L. Spontaneous impulse activity of rat retinal ganglion cells in prenatal life. Science 242, 90–91 (1988).

    Article  CAS  PubMed  Google Scholar 

  4. Meister, M., Wong, R. O., Baylor, D. A. & Shatz, C. J. Synchronous bursts of action potentials in ganglion cells of the developing mammalian retina. Science 252, 939–943 (1991).

    Article  CAS  PubMed  Google Scholar 

  5. Tritsch, N. X., Yi, E., Gale, J. E., Glowatzki, E. & Bergles, D. E. The origin of spontaneous activity in the developing auditory system. Nature 450, 50–55 (2007). The first description of spontaneous correlated activity in the developing cochlea. This study uses a combination of physiology and imaging techniques to implicate release of ATP in the generation of correlated activity.

    Article  CAS  PubMed  Google Scholar 

  6. Torborg, C. L. & Feller, M. B. Spontaneous patterned retinal activity and the refinement of retinal projections. Prog. Neurobiol. 76, 213–235 (2005).

    Article  PubMed  Google Scholar 

  7. Forsythe, I. D. Hearing: a fantasia on Kolliker's organ. Nature 450, 43–44 (2007).

    Article  CAS  PubMed  Google Scholar 

  8. Kandler, K., Clause, A. & Noh, J. Tonotopic reorganization of developing auditory brainstem circuits. Nature Neurosci. 12, 711–717 (2009).

    Article  CAS  PubMed  Google Scholar 

  9. Landmesser, L. T. & O'Donovan, M. J. Activation patterns of embryonic chick hind limb muscles recorded in ovo and in an isolated spinal cord preparation. J. Physiol. 347, 189–204 (1984).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Hanson, M. G., Milner, L. D. & Landmesser, L. T. Spontaneous rhythmic activity in early chick spinal cord influences distinct motor axon pathfinding decisions. Brain Res. Rev. 57, 77–85 (2008).

    Article  PubMed  Google Scholar 

  11. Gonzalez-Islas, C. & Wenner, P. Spontaneous network activity in the embryonic spinal cord regulates AMPAergic and GABAergic synaptic strength. Neuron 49, 563–575 (2006). Although this is not the first demonstration of homeostatic regulation of spinal cord activity, the authors showed that spontaneous network activity influences the relative strength of excitatory and inhibitory synapses. It also demonstrated homeostatic regulation of synaptic strength in an intact circuit.

    Article  CAS  PubMed  Google Scholar 

  12. Myers, C. P. et al. Cholinergic input is required during embryonic development to mediate proper assembly of spinal locomotor circuits. Neuron 46, 37–49 (2005).

    Article  CAS  PubMed  Google Scholar 

  13. Marder, E. & Rehm, K. J. Development of central pattern generating circuits. Curr. Opin. Neurobiol. 15, 86–93 (2005).

    Article  CAS  PubMed  Google Scholar 

  14. Ben-Ari, Y., Cherubini, E., Corradetti, R. & Gaiarsa, J. L. Giant synaptic potentials in immature rat CA3 hippocampal neurones. J. Physiol. 416, 303–325 (1989).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Garaschuk, O., Hanse, E. & Konnerth, A. Developmental profile and synaptic origin of early network oscillations in the CA1 region of rat neonatal hippocampus. J. Physiol. 507, 219–236 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Garaschuk, O., Linn, J., Eilers, J. & Konnerth, A. Large-scale oscillatory calcium waves in the immature cortex. Nature Neurosci. 3, 452–459 (2000).

    Article  CAS  PubMed  Google Scholar 

  17. 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 

  18. Gust, J., Wright, J. J., Pratt, E. B. & Bosma, M. M. Development of synchronized activity of cranial motor neurons in the segmented embryonic mouse hindbrain. J. Physiol. 550, 123–133 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Rockhill, W., Kirkman, J. L. & Bosma, M. M. Spontaneous activity in the developing mouse midbrain driven by an external pacemaker. Dev. Neurobiol. 69, 689–704 (2009).

    Article  CAS  PubMed  Google Scholar 

  20. Watt, A. J. et al. Traveling waves in developing cerebellar cortex mediated by asymmetrical Purkinje cell connectivity. Nature Neurosci. 12, 463–473 (2009). This study used various physiological and modelling techniques to describe the phenomenon of and mechanisms underlying spontaneous network activity in the developing cerebellum.

    Article  CAS  PubMed  Google Scholar 

  21. Moody, W. J. & Bosma, M. M. Ion channel development, spontaneous activity, and activity-dependent development in nerve and muscle cells. Physiol. Rev. 85, 883–941 (2005). This comprehensive review includes detailed descriptions of the physiological changes underlying spontaneous activity in developing circuits.

    Article  CAS  PubMed  Google Scholar 

  22. Mohajerani, M. H. & Cherubini, E. Role of giant depolarizing potentials in shaping synaptic currents in the developing hippocampus. Crit. Rev. Neurobiol. 18, 13–23 (2006).

    Article  CAS  PubMed  Google Scholar 

  23. Khazipov, R. & Luhmann, H. J. Early patterns of electrical activity in the developing cerebral cortex of humans and rodents. Trends Neurosci. 29, 414–418 (2006). This review provides an overview of the mechanisms underlying spontaneous network activation in the developing neocortex, a circuit not covered in our Review.

    Article  CAS  PubMed  Google Scholar 

  24. Wong, R. O., Meister, M. & Shatz, C. J. Transient period of correlated bursting activity during development of the mammalian retina. Neuron 11, 923–938 (1993).

    Article  CAS  PubMed  Google Scholar 

  25. Mooney, R., Penn, A. A., Gallego, R. & Shatz, C. J. Thalamic relay of spontaneous retinal activity prior to vision. Neuron 17, 863–874 (1996).

    Article  CAS  PubMed  Google Scholar 

  26. Weliky, M. & Katz, L. C. Correlational structure of spontaneous neuronal activity in the developing lateral geniculate nucleus in vivo. Science 285, 599–604 (1999).

    Article  CAS  PubMed  Google Scholar 

  27. Hanganu, I. L., Ben-Ari, Y. & Khazipov, R. Retinal waves trigger spindle bursts in the neonatal rat visual cortex. J. Neurosci. 26, 6728–6736 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Hamburger, V. Some aspects of the embryology of behavior. Q. Rev. Biol. 38, 342–365 (1963).

    Article  CAS  PubMed  Google Scholar 

  29. Provine, R. R. Ontogeny of bioelectric activity in the spinal cord of the chick embryo and its behavioral implications. Brain Res. 41, 365–378 (1972).

    Article  CAS  PubMed  Google Scholar 

  30. Milner, L. D. & Landmesser, L. T. Cholinergic and GABAergic inputs drive patterned spontaneous motoneuron activity before target contact. J. Neurosci. 19, 3007–3022 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Yvert, B., Branchereau, P. & Meyrand, P. Multiple spontaneous rhythmic activity patterns generated by the embryonic mouse spinal cord occur within a specific developmental time window. J. Neurophysiol. 91, 2101–2109 (2004).

    Article  PubMed  Google Scholar 

  32. Ren, J. & Greer, J. J. Ontogeny of rhythmic motor patterns generated in the embryonic rat spinal cord. J. Neurophysiol. 89, 1187–1195 (2003).

    Article  PubMed  Google Scholar 

  33. Xu, H., Whelan, P. J. & Wenner, P. Development of an inhibitory interneuronal circuit in the embryonic spinal cord. J. Neurophysiol. 93, 2922–2933 (2005).

    Article  PubMed  Google Scholar 

  34. Bekoff, A. Ontogeny of leg motor output in the chick embryo: a neural analysis. Brain Res. 106, 271–291 (1976).

    Article  CAS  PubMed  Google Scholar 

  35. Crepel, V. et al. A parturition-associated nonsynaptic coherent activity pattern in the developing hippocampus. Neuron 54, 105–120 (2007).

    Article  CAS  PubMed  Google Scholar 

  36. Allene, C. et al. Sequential generation of two distinct synapse-driven network patterns in developing neocortex. J. Neurosci. 28, 12851–12863 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Leinekugel, X., Medina, I., Khalilov, I., Ben-Ari, Y. & Khazipov, R. Ca2+ oscillations mediated by the synergistic excitatory actions of GABAA and NMDA receptors in the neonatal hippocampus. Neuron 18, 243–255 (1997).

    Article  CAS  PubMed  Google Scholar 

  38. Gummer, A. W. & Mark, R. F. Patterned neural activity in brain stem auditory areas of a prehearing mammal, the tammar wallaby (Macropus eugenii). Neuroreport 5, 685–688 (1994).

    Article  CAS  PubMed  Google Scholar 

  39. Jones, T. A., Jones, S. M. & Paggett, K. C. Primordial rhythmic bursting in embryonic cochlear ganglion cells. J. Neurosci. 21, 8129–8135 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Jones, T. A., Leake, P. A., Snyder, R. L., Stakhovskaya, O. & Bonham, B. Spontaneous discharge patterns in cochlear spiral ganglion cells before the onset of hearing in cats. J. Neurophysiol. 98, 1898–1908 (2007).

    Article  PubMed  Google Scholar 

  41. Lippe, W. R. Rhythmic spontaneous activity in the developing avian auditory system. J. Neurosci. 14, 1486–1495 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Harris-Warrick, R. M. Voltage-sensitive ion channels in rhythmic motor systems. Curr. Opin. Neurobiol. 12, 646–651 (2002).

    Article  CAS  PubMed  Google Scholar 

  43. Biel, M., Wahl-Schott, C., Michalakis, S. & Zong, X. Hyperpolarization-activated cation channels: from genes to function. Physiol. Rev. 89, 847–885 (2009).

    Article  CAS  PubMed  Google Scholar 

  44. Rybak, I. A., Abdala, A. P., Markin, S. N., Paton, J. F. & Smith, J. C. Spatial organization and state-dependent mechanisms for respiratory rhythm and pattern generation. Prog. Brain Res. 165, 201–220 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  45. Bond, C. T., Maylie, J. & Adelman, J. P. SK channels in excitability, pacemaking and synaptic integration. Curr. Opin. Neurobiol. 15, 305–311 (2005).

    Article  CAS  PubMed  Google Scholar 

  46. Raman, I. M. & Bean, B. P. Resurgent sodium current and action potential formation in dissociated cerebellar Purkinje neurons. J. Neurosci. 17, 4517–4526 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Ben-Ari, Y., Gaiarsa, J. L., Tyzio, R. & Khazipov, R. GABA: a pioneer transmitter that excites immature neurons and generates primitive oscillations. Physiol. Rev. 87, 1215–1284 (2007). This review describes the many functions of depolarizing GABA throughout the development of the nervious system, including the generation of giant depolarizing potentials.

    Article  CAS  PubMed  Google Scholar 

  48. Sipila, S. T. & Kaila, K. GABAergic control of CA3-driven network events in the developing hippocampus. Res. Probl. Cell Differ. 44, 99–121 (2008).

    Article  CAS  Google Scholar 

  49. Sipila, S. T., Huttu, K., Voipio, J. & Kaila, K. Intrinsic bursting of immature CA3 pyramidal neurons and consequent giant depolarizing potentials are driven by a persistent Na+ current and terminated by a slow Ca2+ -activated K+ current. Eur. J. Neurosci. 23, 2330–2338 (2006).

    Article  PubMed  Google Scholar 

  50. Sipila, S. T., Huttu, K., Soltesz, I., Voipio, J. & Kaila, K. Depolarizing GABA acts on intrinsically bursting pyramidal neurons to drive giant depolarizing potentials in the immature hippocampus. J. Neurosci. 25, 5280–5289 (2005). This study highlights how the spontaneous bursting in CA3 pyramidal cells coupled with network interactions is responsible for initiating events in the developing hippocampus.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  51. Lischalk, J. W., Easton, C. R. & Moody, W. J. Bilaterally propagating waves of spontaneous activity arising from discrete pacemakers in the neonatal mouse cerebral cortex. Dev. Neurobiol. 69, 407–414 (2009).

    Article  PubMed  Google Scholar 

  52. Butts, D. A., Feller, M. B., Shatz, C. J. & Rokhsar, D. S. Retinal waves are governed by collective network properties. J. Neurosci. 19, 3580–3593 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Godfrey, K. B. & Swindale, N. V. Retinal wave behavior through activity-dependent refractory periods. PLoS Comput. Biol. 3, e245 (2007).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  54. Zheng, J., Lee, S. & Zhou, Z. J. A transient network of intrinsically bursting starburst cells underlies the generation of retinal waves. Nature Neurosci. 9, 363–371 (2006). This important study described pacemaker-like properties in an excitatory interneuron involved in retinal wave generation.

    Article  CAS  PubMed  Google Scholar 

  55. Zhou, Z. J. The function of the cholinergic system in the developing mammalian retina. Prog. Brain Res. 131, 599–613 (2001).

    Article  CAS  PubMed  Google Scholar 

  56. Zheng, J. J., Lee, S. & Zhou, Z. J. A developmental switch in the excitability and function of the starburst network in the mammalian retina. Neuron 44, 851–864 (2004).

    Article  CAS  PubMed  Google Scholar 

  57. Lancaster, B. & Nicoll, R. A. Properties of two calcium-activated hyperpolarizations in rat hippocampal neurones. J. Physiol. 389, 187–203 (1987).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Sah, P. & Isaacson, J. S. Channels underlying the slow afterhyperpolarization in hippocampal pyramidal neurons: neurotransmitters modulate the open probability. Neuron 15, 435–441 (1995).

    Article  CAS  PubMed  Google Scholar 

  59. Sah, P. Ca2+-activated K+ currents in neurones: types, physiological roles and modulation. Trends Neurosci. 19, 150–154 (1996).

    Article  CAS  PubMed  Google Scholar 

  60. Sah, P. & Faber, E. S. Channels underlying neuronal calcium-activated potassium currents. Prog. Neurobiol. 66, 345–353 (2002).

    Article  CAS  PubMed  Google Scholar 

  61. Vogalis, F., Storm, J. F. & Lancaster, B. SK channels and the varieties of slow after-hyperpolarizations in neurons. Eur. J. Neurosci. 18, 3155–3166 (2003).

    Article  PubMed  Google Scholar 

  62. Goaillard, J. M. & Vincent, P. Serotonin suppresses the slow afterhyperpolarization in rat intralaminar and midline thalamic neurones by activating 5-HT(7) receptors. J. Physiol. 541, 453–465 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Neylon, C. B., Fowler, C. J. & Furness, J. B. Regulation of the slow afterhyperpolarization in enteric neurons by protein kinase A. Auton. Neurosci. 126–127, 258–263 (2006).

  64. Stellwagen, D., Shatz, C. J. & Feller, M. B. Dynamics of retinal waves are controlled by cyclic AMP. Neuron 24, 673–685 (1999).

    Article  CAS  PubMed  Google Scholar 

  65. Hennig, M. H., Adams, C., Willshaw, D. & Sernagor, E. Early-stage waves in the retinal network emerge close to a critical state transition between local and global functional connectivity. J. Neurosci. 29, 1077–1086 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Hanson, M. G. & Landmesser, L. T. Characterization of the circuits that generate spontaneous episodes of activity in the early embryonic mouse spinal cord. J. Neurosci. 23, 587–600 (2003). This paper was crucial for determining the changing circuits that mediate spontaneous network activity in the mouse spinal cord.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Wenner, P. & O'Donovan, M. J. Mechanisms that initiate spontaneous network activity in the developing chick spinal cord. J. Neurophysiol. 86, 1481–1498 (2001).

    Article  CAS  PubMed  Google Scholar 

  68. Arai, Y., Mentis, G. Z., Wu, J. Y. & O'Donovan, M. J. Ventrolateral origin of each cycle of rhythmic activity generated by the spinal cord of the chick embryo. PLoS ONE 2, e417 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  69. Chub, N. & O'Donovan, M. J. Post-episode depression of GABAergic transmission in spinal neurons of the chick embryo. J. Neurophysiol. 85, 2166–2176 (2001).

    Article  CAS  PubMed  Google Scholar 

  70. Fedirchuk, B. et al. Spontaneous network activity transiently depresses synaptic transmission in the embryonic chick spinal cord. J. Neurosci. 19, 2102–2112 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Marchetti, C., Tabak, J., Chub, N., O'Donovan, M. J. & Rinzel, J. Modeling spontaneous activity in the developing spinal cord using activity-dependent variations of intracellular chloride. J. Neurosci. 25, 3601–3612 (2005). This study combined physiological recordings and computational modelling to describe how GABAergic signalling could dictate the frequency of network events in developing chick spinal cord.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Tabak, J., Senn, W., O'Donovan, M. J. & Rinzel, J. Modeling of spontaneous activity in developing spinal cord using activity-dependent depression in an excitatory network. J. Neurosci. 20, 3041–3056 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Chub, N., Mentis, G. Z. & O'Donovan, M. J. Chloride-sensitive MEQ fluorescence in chick embryo motoneurons following manipulations of chloride and during spontaneous network activity. J. Neurophysiol. 95, 323–330 (2006).

    Article  CAS  PubMed  Google Scholar 

  74. Ben-Ari, Y. Excitatory actions of GABA during development: the nature of the nurture. Nature Rev. Neurosci. 3, 728–739 (2002).

    Article  CAS  Google Scholar 

  75. Blaesse, P., Airaksinen, M. S., Rivera, C. & Kaila, K. Cation-chloride cotransporters and neuronal function. Neuron 61, 820–838 (2009).

    Article  CAS  PubMed  Google Scholar 

  76. Zhang, L. L., Pathak, H. R., Coulter, D. A., Freed, M. A. & Vardi, N. Shift of intracellular chloride concentration in ganglion and amacrine cells of developing mouse retina. J. Neurophysiol. 95, 2404–2416 (2006).

    Article  CAS  PubMed  Google Scholar 

  77. Leitch, E., Coaker, J., Young, C., Mehta, V. & Sernagor, E. GABA type-A activity controls its own developmental polarity switch in the maturing retina. J. Neurosci. 25, 4801–4805 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Sernagor, E., Young, C. & Eglen, S. J. Developmental modulation of retinal wave dynamics: shedding light on the GABA saga. J. Neurosci. 23, 7621–7629 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Wang, C. T. et al. GABA(A) receptor-mediated signaling alters the structure of spontaneous activity in the developing retina. J. Neurosci. 27, 9130–9140 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. O'Donovan, M. J., Chub, N. & Wenner, P. Mechanisms of spontaneous activity in developing spinal networks. J. Neurobiol. 37, 131–145 (1998).

    Article  CAS  PubMed  Google Scholar 

  81. Nishimaru, H., Restrepo, C. E., Ryge, J., Yanagawa, Y. & Kiehn, O. 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 

  82. 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 

  83. Mentis, G. Z., Siembab, V. C., Zerda, R., O'Donovan, M. J. & Alvarez, F. J. Primary afferent synapses on developing and adult Renshaw cells. J. Neurosci. 26, 13297–13310 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Demarque, M. et al. Paracrine intercellular communication by a Ca2+- and SNARE-independent release of GABA and glutamate prior to synapse formation. Neuron 36, 1051–1061 (2002).

    Article  CAS  PubMed  Google Scholar 

  85. LoTurco, J. J., Owens, D. F., Heath, M. J., Davis, M. B. & Kriegstein, A. R. GABA and glutamate depolarize cortical progenitor cells and inhibit DNA synthesis. Neuron 15, 1287–1298 (1995).

    Article  CAS  PubMed  Google Scholar 

  86. Manent, J. B. et al. A noncanonical release of GABA and glutamate modulates neuronal migration. J. Neurosci. 25, 4755–4765 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Blankenship, A. G. et al. Synaptic and extrasynaptic factors governing glutamatergic retinal waves. Neuron 62, 230–241 (2009). This recent study implicated glutamate spillover in retinal waves and showed that the absence of glutamatergic waves prevented the cessation of cholinergic retinal waves.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Chen, S. & Diamond, J. S. Synaptically released glutamate activates extrasynaptic NMDA receptors on cells in the ganglion cell layer of rat retina. J. Neurosci. 22, 2165–2173 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. DeVries, S. H., Li, W. & Saszik, S. Parallel processing in two transmitter microenvironments at the cone photoreceptor synapse. Neuron 50, 735–748 (2006).

    Article  CAS  PubMed  Google Scholar 

  90. Veruki, M. L., Morkve, S. H. & Hartveit, E. Activation of a presynaptic glutamate transporter regulates synaptic transmission through electrical signaling. Nature Neurosci. 9, 1388–1396 (2006).

    Article  CAS  PubMed  Google Scholar 

  91. Sernagor, E., Eglen, S. J. & O'Donovan, M. J. Differential effects of acetylcholine and glutamate blockade on the spatiotemporal dynamics of retinal waves. J. Neurosci. 20, RC56 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Demarque, M. et al. Glutamate transporters prevent the generation of seizures in the developing rat neocortex. J. Neurosci. 24, 3289–3294 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Milh, M., Becq, H., Villeneuve, N., Ben-Ari, Y. & Aniksztejn, L. Inhibition of glutamate transporters results in a “suppression-burst” pattern and partial seizures in the newborn rat. Epilepsia 48, 169–174 (2007).

    Article  CAS  PubMed  Google Scholar 

  94. Cattani, A. A., Bonfardin, V. D., Represa, A., Ben-Ari, Y. & Aniksztejn, L. Generation of slow network oscillations in the developing rat hippocampus after blockade of glutamate uptake. J. Neurophysiol. 98, 2324–2336 (2007).

    Article  CAS  PubMed  Google Scholar 

  95. Sharifullina, E. & Nistri, A. Glutamate uptake block triggers deadly rhythmic bursting of neonatal rat hypoglossal motoneurons. J. Physiol. 572, 407–423 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Bansal, A. et al. Mice lacking specific nicotinic acetylcholine receptor subunits exhibit dramatically altered spontaneous activity patterns and reveal a limited role for retinal waves in forming ON and OFF circuits in the inner retina. J. Neurosci. 20, 7672–7681 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Syed, M. M., Lee, S., Zheng, J. & Zhou, Z. J. Stage-dependent dynamics and modulation of spontaneous waves in the developing rabbit retina. J. Physiol. 560, 533–549 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Singer, J. H., Mirotznik, R. R. & Feller, M. B. Potentiation of L-type calcium channels reveals nonsynaptic mechanisms that correlate spontaneous activity in the developing mammalian retina. J. Neurosci. 21, 8514–8522 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Vessey, J. P. et al. Carbenoxolone inhibition of voltage-gated Ca channels and synaptic transmission in the retina. J. Neurophysiol. 92, 1252–1256 (2004).

    Article  CAS  PubMed  Google Scholar 

  100. Takeda, Y., Ward, S. M., Sanders, K. M. & Koh, S. D. Effects of the gap junction blocker glycyrrhetinic acid on gastrointestinal smooth muscle cells. Am. J. Physiol. Gastrointest. Liver Physiol. 288, G832–G841 (2005).

    Article  CAS  PubMed  Google Scholar 

  101. Sheu, S. J., Bee, Y. S. & Chen, C. H. Resveratrol and large-conductance calcium-activated potassium channels in the protection of human retinal pigment epithelial cells. J. Ocul. Pharmacol. Ther. 24, 551–555 (2008).

    Article  CAS  PubMed  Google Scholar 

  102. Wu, S. N., Jan, C. R. & Chiang, H. T. Fenamates stimulate BKCa channel osteoblast-like MG-63 cells activity in the human. J. Investig. Med. 49, 522–533 (2001).

    Article  CAS  PubMed  Google Scholar 

  103. Tovar, K. R., Maher, B. J. & Westbrook, G. L. Direct actions of carbenoxolone on synaptic transmission and neuronal membrane properties. J. Neurophysiol. 102, 974–978 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  104. Chang, Q., Gonzalez, M., Pinter, M. J. & Balice-Gordon, R. J. Gap junctional coupling and patterns of connexin expression among neonatal rat lumbar spinal motor neurons. J. Neurosci. 19, 10813–10828 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Personius, K. E., Chang, Q., Mentis, G. Z., O'Donovan, M. J. & Balice-Gordon, R. J. Reduced gap junctional coupling leads to uncorrelated motor neuron firing and precocious neuromuscular synapse elimination. Proc. Natl Acad. Sci. USA 104, 11808–11813 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Torborg, C. L., Hansen, K. A. & Feller, M. B. High frequency, synchronized bursting drives eye-specific segregation of retinogeniculate projections. Nature Neurosci. 8, 72–78 (2005).

    Article  CAS  PubMed  Google Scholar 

  107. Hansen, K. A., Torborg, C. L., Elstrott, J. & Feller, M. B. Expression and function of the neuronal gap junction protein connexin 36 in developing mammalian retina. J. Comp. Neurol. 493, 309–320 (2005).

    Article  CAS  PubMed  Google Scholar 

  108. Turrigiano, G. Maintaining your youthful spontaneity: microcircuit homeostasis in the embryonic spinal cord. Neuron 49, 481–483 (2006).

    Article  CAS  PubMed  Google Scholar 

  109. Chub, N. & O'Donovan, M. J. Blockade and recovery of spontaneous rhythmic activity after application of neurotransmitter antagonists to spinal networks of the chick embryo. J. Neurosci. 18, 294–306 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Wilhelm, J. C. & Wenner, P. GABAA transmission is a critical step in the process of triggering homeostatic increases in quantal amplitude. Proc. Natl Acad. Sci. USA 105, 11412–11417 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Wilhelm, J. C., Rich, M. M. & Wenner, P. Compensatory changes in cellular excitability, not synaptic scaling, contribute to homeostatic recovery of embryonic network activity. Proc. Natl Acad. Sci. USA 106, 6760–6765 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Stacy, R. C., Demas, J., Burgess, R. W., Sanes, J. R. & Wong, R. O. Disruption and recovery of patterned retinal activity in the absence of acetylcholine. J. Neurosci. 25, 9347–9357 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. McLaughlin, T., Torborg, C. L., Feller, M. B. & O'Leary, D. D. Retinotopic map refinement requires spontaneous retinal waves during a brief critical period of development. Neuron 40, 1147–1160 (2003).

    Article  CAS  PubMed  Google Scholar 

  114. Sun, C., Warland, D. K., Ballesteros, J. M., van der List, D. & Chalupa, L. M. Retinal waves in mice lacking the β2 subunit of the nicotinic acetylcholine receptor. Proc. Natl Acad. Sci. USA 105, 13638–13643 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Stafford, B. K., Sher, A., Litke, A. M. & Feldheim, D. A. Spatial-temporal patterns of retinal waves underlying activity-dependent refinement of retinofugal projections. Neuron 64, 200–212 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Torborg, C., Wang, C. T., Muir-Robinson, G. & Feller, M. B. L-type calcium channel agonist induces correlated depolarizations in mice lacking the β2 subunit nAChRs. Vision Res. 44, 3347–3355 (2004).

    Article  CAS  PubMed  Google Scholar 

  117. Mochida, H., Sato, K. & Momose-Sato, Y. Switching of the transmitters that mediate hindbrain correlated activity in the chick embryo. Eur. J. Neurosci. 29, 14–30 (2009).

    Article  PubMed  Google Scholar 

  118. Sipila, S. T. et al. Compensatory enhancement of intrinsic spiking upon NKCC1 disruption in neonatal hippocampus. J. Neurosci. 29, 6982–6988 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Pfeffer, C. K. et al. NKCC1-dependent GABAergic excitation drives synaptic network maturation during early hippocampal development. J. Neurosci. 29, 3419–3430 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Galindo, R. & Valenzuela, C. F. Immature hippocampal neuronal networks do not develop tolerance to the excitatory actions of ethanol. Alcohol 40, 111–118 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Stromland, K. Visual impairment and ocular abnormalities in children with fetal alcohol syndrome. Addict. Biol. 9, 153–157; discussion 159–160 (2004).

    Article  PubMed  CAS  Google Scholar 

  122. Medina, A. E., Krahe, T. E. & Ramoa, A. S. Early alcohol exposure induces persistent alteration of cortical columnar organization and reduced orientation selectivity in the visual cortex. J. Neurophysiol. 93, 1317–1325 (2005).

    Article  CAS  PubMed  Google Scholar 

  123. Tyzio, R. et al. Maternal oxytocin triggers a transient inhibitory switch in GABA signaling in the fetal brain during delivery. Science 314, 1788–1792 (2006).

    Article  CAS  PubMed  Google Scholar 

  124. Leinekugel, X. Developmental patterns and plasticities: the hippocampal model. J. Physiol. (Paris) 97, 27–37 (2003).

    Article  CAS  Google Scholar 

  125. Leinekugel, X. et al. Correlated bursts of activity in the neonatal hippocampus in vivo. Science 296, 2049–2052 (2002).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

Support provided by National Science Foundation grant IOS-0818983 (M.F.) and US National Institutes of Health grants RO1EY013528 (M.F.) and F31NS058167 (A.B.). The authors thank D. Bergles and P. Wenner for critical comments on the manuscript.

Author information

Authors and Affiliations

  1. Neurosciences Graduate Program, University of California, San Diego, La Jolla, 92093, California, USA

    Aaron G. Blankenship

  2. Department of Molecular and Cell Biology, and Helen Wills Neuroscience Institute, University of California, Berkeley, Berkeley, 94720, California, USA

    Marla B. Feller

Authors
  1. Aaron G. Blankenship
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Marla B. Feller
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Marla B. Feller.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary information S1 (movie)

Spontaneous network activity in a postnatal day 10 mouse retina. (MOV 9445 kb)

Related links

Related links

FURTHER INFORMATION

Marla B. Feller's homepage

Glossary

Extrasynaptic transmission

Neurotransmitter-mediated signalling through a pathway other than a direct synaptic connection. One example is spillover, in which synaptically released neurotransmitter diffuses out of the synapse and activates extrasynaptic receptors or synaptic receptors located in neighbouring synapses. A second example is volume transmission, in which neurotransmitter is released directly into the non-synaptic extracellular space.

Gap junctions

Intercellular channels composed of connexin proteins that are the basis of electrical synapses between neurons.

Retinal ganglion cells

The projection neurons of the retina, the axons of which form the optic nerve.

Central pattern generator

A neural circuit that produces self-sustaining patterns of behaviour independently of sensory input.

Pacemaker-like neuron

In the adult nervous system, pacemaker neurons possess a set of ion channels that lead to regular patterns of depolarization and hyperpolarization. In developing circuits, pacemaker-like neurons are neurons with unstable membrane potentials, the pacemaker properties of which also depend on network interactions.

Amacrine cell

A retinal interneuron located in the inner nuclear or ganglion cell layer of the retina that provides local inhibition in the adult retina.

Renshaw cell

A GABAergic interneuron that receives excitatory input from motor neurons.

Bipolar cell

An interneuron of the retina that provides excitatory glutamatergic input to retinal ganglion cells. In the adult retina, bipolar cells receive input from photoreceptors.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Blankenship, A., Feller, M. Mechanisms underlying spontaneous patterned activity in developing neural circuits. Nat Rev Neurosci 11, 18–29 (2010). https://doi.org/10.1038/nrn2759

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrn2759

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing