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

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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.


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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).

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