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Neuronal activity is required for the development of specific cortical interneuron subtypes

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Abstract

Electrical activity has been shown to regulate development in a variety of species and in various structures1, including the retina2,3,4, spinal cord5,6 and cortex5. Within the mammalian cortex specifically, the development of dendrites and commissural axons in pyramidal cells is activity-dependent7,8. However, little is known about the developmental role of activity in the other major cortical population of neurons, the GABA-producing interneurons. These neurons are morphologically and functionally heterogeneous and efforts over the past decade have focused on determining the mechanisms that contribute to this diversity9,10,11. It was recently discovered that 30% of all cortical interneurons arise from a relatively novel source within the ventral telencephalon, the caudal ganglionic eminence (CGE)11,12. Owing to their late birth date, these interneurons populate the cortex only after the majority of other interneurons and pyramidal cells are already in place and have started to functionally integrate. Here we demonstrate in mice that for CGE-derived reelin (Re)-positive and calretinin (Cr)-positive (but not vasoactive intestinal peptide (VIP)-positive) interneurons12,13, activity is essential before postnatal day 3 for correct migration, and that after postnatal day 3, glutamate-mediated activity controls the development of their axons and dendrites. Furthermore, we show that the engulfment and cell motility 1 gene (Elmo1)14, a target of the transcription factor distal-less homeobox 1 (Dlx1)15, is selectively expressed in Re+ and Cr+ interneurons and is both necessary and sufficient for activity-dependent interneuron migration. Our findings reveal a selective requirement for activity in shaping the cortical integration of specific neuronal subtypes.

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Figure 1: Defective morphology of Cr + and Re + interneuron subtypes resulting from Kir2.1 expression.
Figure 2: Neuronal activity is essential for the proper laminar migration of selective interneuron subtypes.
Figure 3: Specific interneuron subtypes require activity for migration and morphological maturation at two distinct stages of development.
Figure 4: Ionotropic glutamate receptor blockade mimics the effects of Kir2.1 expression on Cr + and Re + interneuron morphology.
Figure 5: Activity-dependent expression of ELMO1 regulates CGE-derived interneuron migration.

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  • 21 April 2011

    Reference 9 was substituted.

References

  1. Blankenship, A. G. & Feller, M. B. Mechanisms underlying spontaneous patterned activity in developing neural circuits. Nature Rev. Neurosci. 11, 18–29 (2010)

    CAS  Article  Google Scholar 

  2. Wong, R. O., Chernjavsky, A., Smith, S. J. & Shatz, C. J. Early functional neural networks in the developing retina. Nature 374, 716–718 (1995)

    ADS  CAS  Article  Google Scholar 

  3. Penn, A. A., Riquelme, P. A., Feller, M. B. & Shatz, C. J. Competition in retinogeniculate patterning driven by spontaneous activity. Science 279, 2108–2112 (1998)

    ADS  CAS  Article  Google Scholar 

  4. Huberman, A. D. et al. Architecture and activity-mediated refinement of axonal projections from a mosaic of genetically identified retinal ganglion cells. Neuron 59, 425–438 (2008)

    CAS  Article  Google Scholar 

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

    ADS  CAS  Article  Google Scholar 

  6. Root, C. M., Velazquez-Ulloa, N. A., Monsalve, G. C., Minakova, E. & Spitzer, N. C. Embryonically expressed GABA and glutamate drive electrical activity regulating neurotransmitter specification. J. Neurosci. 28, 4777–4784 (2008)

    CAS  Article  Google Scholar 

  7. Cancedda, L., Fiumelli, H., Chen, K. & Poo, M. M. Excitatory GABA action is essential for morphological maturation of cortical neurons in vivo . J. Neurosci. 27, 5224–5235 (2007)

    CAS  Article  Google Scholar 

  8. Wang, C. L. et al. Activity-dependent development of callosal projections in the somatosensory cortex. J. Neurosci. 27, 11334–11342 (2007)

    CAS  Article  Google Scholar 

  9. Bortone, D. & Polleux, F. KCC2 expression promotes the termination of cortical interneuron migration in a voltage-sensitive calcium-dependent manner. Neuron 62, 53–71 (2009)

    CAS  Article  Google Scholar 

  10. Ascoli, G. A. et al. Petilla terminology: nomenclature of features of GABAergic interneurons of the cerebral cortex. Nature Rev. Neurosci. 9, 557–568 (2008)

    CAS  Article  Google Scholar 

  11. Batista-Brito, R. & Fishell, G. The developmental integration of cortical interneurons into a functional network. Curr. Top. Dev. Biol. 87, 81–118 (2009)

    Article  Google Scholar 

  12. Miyoshi, G. et al. Genetic fate mapping reveals that the caudal ganglionic eminence produces a large and diverse population of superficial cortical interneurons. J. Neurosci. 30, 1582–1594 (2010)

    CAS  Article  Google Scholar 

  13. Karube, F., Kubota, Y. & Kawaguchi, Y. Axon branching and synaptic bouton phenotypes in GABAergic nonpyramidal cell subtypes. J. Neurosci. 24, 2853–2865 (2004)

    CAS  Article  Google Scholar 

  14. Gumienny, T. L. et al. CED-12/ELMO, a novel member of the CrkII/Dock180/Rac pathway, is required for phagocytosis and cell migration. Cell 107, 27–41 (2001)

    CAS  Article  Google Scholar 

  15. Cobos, I., Borello, U. & Rubenstein, J. L. Dlx transcription factors promote migration through repression of axon and dendrite growth. Neuron 54, 873–888 (2007)

    CAS  Article  Google Scholar 

  16. Allene, C. & Cossart, R. Early NMDA receptor-driven waves of activity in the developing neocortex: physiological or pathological network oscillations? J. Physiol. (Lond.) 588, 83–91 (2010)

    CAS  Article  Google Scholar 

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

    CAS  Article  Google Scholar 

  18. Dupont, E., Hanganu, I. L., Kilb, W., Hirsch, S. & Luhmann, H. J. Rapid developmental switch in the mechanisms driving early cortical columnar networks. Nature 439, 79–83 (2006)

    ADS  CAS  Article  Google Scholar 

  19. Stenman, J., Toresson, H. & Campbell, K. Identification of two distinct progenitor populations in the lateral ganglionic eminence: implications for striatal and olfactory bulb neurogenesis. J. Neurosci. 23, 167–174 (2003)

    CAS  Article  Google Scholar 

  20. Yu, C. R. et al. Spontaneous neural activity is required for the establishment and maintenance of the olfactory sensory map. Neuron 42, 553–566 (2004)

    CAS  Article  Google Scholar 

  21. Yang, J. W., Hanganu-Opatz, I. L., Sun, J. J. & Luhmann, H. J. Three patterns of oscillatory activity differentially synchronize developing neocortical networks in vivo . J. Neurosci. 29, 9011–9025 (2009)

    CAS  Article  Google Scholar 

  22. 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)

    CAS  Article  Google Scholar 

  23. 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. (Lond.) 577, 155–167 (2006)

    CAS  Article  Google Scholar 

  24. Manent, J. B., Jorquera, I., Ben-Ari, Y., Aniksztejn, L. & Represa, A. Glutamate acting on AMPA but not NMDA receptors modulates the migration of hippocampal interneurons. J. Neurosci. 26, 5901–5909 (2006)

    CAS  Article  Google Scholar 

  25. Stone, T. W. Neuropharmacology of quinolinic and kynurenic acids. Pharmacol. Rev. 45, 309–379 (1993)

    CAS  PubMed  Google Scholar 

  26. Anderson, S. A., Eisenstat, D. D., Shi, L. & Rubenstein, J. L. Interneuron migration from basal forebrain to neocortex: dependence on Dlx genes. Science 278, 474–476 (1997)

    ADS  CAS  Article  Google Scholar 

  27. Wonders, C. P. & Anderson, S. A. The origin and specification of cortical interneurons. Nature Rev. Neurosci. 7, 687–696 (2006)

    CAS  Article  Google Scholar 

  28. Cobos, I. et al. Mice lacking Dlx1 show subtype-specific loss of interneurons, reduced inhibition and epilepsy. Nature Neurosci. 8, 1059–1068 (2005)

    CAS  Article  Google Scholar 

  29. Ravichandran, K. S. & Lorenz, U. Engulfment of apoptotic cells: signals for a good meal. Nature Rev. Immunol. 7, 964–974 (2007)

    CAS  Article  Google Scholar 

  30. Park, D. et al. BAI1 is an engulfment receptor for apoptotic cells upstream of the ELMO/Dock180/Rac module. Nature 450, 430–434 (2007)

    ADS  CAS  Article  Google Scholar 

  31. Saito, T. In vivo electroporation in the embryonic mouse central nervous system. Nature Protocols 1, 1552–1558 (2006)

    CAS  Article  Google Scholar 

  32. Butt, S. J. et al. The requirement of Nkx2-1 in the temporal specification of cortical interneuron subtypes. Neuron 59, 722–732 (2008)

    CAS  Article  Google Scholar 

  33. Tamamaki, N. et al. Green fluorescent protein expression and colocalization with calretinin, parvalbumin, and somatostatin in the GAD67-GFP knock-in mouse. J. Comp. Neurol. 467, 60–79 (2003)

    CAS  Article  Google Scholar 

  34. Miyoshi, G., Butt, S. J., Takebayashi, H. & Fishell, G. Physiologically distinct temporal cohorts of cortical interneurons arise from telencephalic Olig2-expressing precursors. J. Neurosci. 27, 7786–7798 (2007)

    CAS  Article  Google Scholar 

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Acknowledgements

We are grateful to R. Batista-Brito, E. Chiappe, R. Cossart, J. Dasen, J. Kaltschmidt, S. Lee, J. Hjerling Leffler, M. Long, D. Pisapia and B. Rudy for comments on the manuscript. We thank L. Yin for technical assistance. We are indebted to K. Ravichandran for providing the ELMO1 constructs. N.V.D.G. and T.K. are both supported by grants from The Patterson Trust. Research in the Fishell laboratory is supported by the National Institutes of Health, National Institute of Mental Health (5RO1MH068469-08 and 2R01MH071679-09), National Institute of Neurological Disorders and Stroke (5R01NS039007-1), New York Stem Cell Science State (NGSG-130) and the Simons Foundation.

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N.V.D.G. and G.F. conceived the project. N.V.D.G. and T.K. designed and carried out the experiments. N.V.D.G. wrote the manuscript with the help of all authors.

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Correspondence to Gord Fishell.

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De Marco García, N., Karayannis, T. & Fishell, G. Neuronal activity is required for the development of specific cortical interneuron subtypes. Nature 472, 351–355 (2011). https://doi.org/10.1038/nature09865

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