IL1RAPL1 controls inhibitory networks during cerebellar development in mice

Authors

  • Frédéric Gambino,

    1. Institut des Neurosciences Cellulaires et Intégratives, UPR3212, Centre National de la Recherche Scientifique, 5 Rue Blaise Pascal, 67084 Strasbourg, France
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    • *

      F.G. and M.K. contributed equally to this work.

  • Marie Kneib,

    1. Institut des Neurosciences Cellulaires et Intégratives, UPR3212, Centre National de la Recherche Scientifique, 5 Rue Blaise Pascal, 67084 Strasbourg, France
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    • *

      F.G. and M.K. contributed equally to this work.

  • Alice Pavlowsky,

    1. Institut Cochin, Centre National de la Recherche Scientifique, Université Paris Descartes, Institut National de la Santé et de la Recherche Médicale, Paris, France
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  • Henriette Skala,

    1. Institut Cochin, Centre National de la Recherche Scientifique, Université Paris Descartes, Institut National de la Santé et de la Recherche Médicale, Paris, France
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  • Stéphane Heitz,

    1. Institut des Neurosciences Cellulaires et Intégratives, UPR3212, Centre National de la Recherche Scientifique, 5 Rue Blaise Pascal, 67084 Strasbourg, France
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  • Nicolas Vitale,

    1. Institut des Neurosciences Cellulaires et Intégratives, UPR3212, Centre National de la Recherche Scientifique, 5 Rue Blaise Pascal, 67084 Strasbourg, France
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  • Bernard Poulain,

    1. Institut des Neurosciences Cellulaires et Intégratives, UPR3212, Centre National de la Recherche Scientifique, 5 Rue Blaise Pascal, 67084 Strasbourg, France
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  • Malik Khelfaoui,

    1. Institut des Neurosciences Cellulaires et Intégratives, UPR3212, Centre National de la Recherche Scientifique, 5 Rue Blaise Pascal, 67084 Strasbourg, France
    2. Institut Cochin, Centre National de la Recherche Scientifique, Université Paris Descartes, Institut National de la Santé et de la Recherche Médicale, Paris, France
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  • Jamel Chelly,

    1. Institut Cochin, Centre National de la Recherche Scientifique, Université Paris Descartes, Institut National de la Santé et de la Recherche Médicale, Paris, France
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  • Pierre Billuart,

    1. Institut Cochin, Centre National de la Recherche Scientifique, Université Paris Descartes, Institut National de la Santé et de la Recherche Médicale, Paris, France
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  • Yann Humeau

    1. Institut des Neurosciences Cellulaires et Intégratives, UPR3212, Centre National de la Recherche Scientifique, 5 Rue Blaise Pascal, 67084 Strasbourg, France
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Dr Y. Humeau, as above.
E-mail: humeau@neurochem.u-strasbg.fr

Abstract

Abnormalities in the formation and function of cerebellar circuitry potentially contribute to cognitive deficits in humans. In the adult, the activity of the sole output neurons of the cerebellar cortex – the Purkinje cells (PCs) – is shaped by the balance of activity between local excitatory and inhibitory circuits. However, how this balance is established during development remains poorly understood. Here, we investigate the role of interleukin-1 receptor accessory protein-like 1 (IL1RAPL1), a protein linked to cognitive function which interacts with neuronal calcium sensor 1 (NCS-1) in the development of mouse cerebellum. Using Il1rapl1-deficient mice, we found that absence of IL1RAPL1 causes a transient disinhibition of deep cerebellar nuclei neurons between postnatal days 10 and 14 (P10/P14). Upstream, in the cerebellar cortex, we found developmental perturbations in the activity level of molecular layer interneurons (MLIs), resulting in the premature appearance of giant GABAA-mediated inhibitory post-synaptic currents capable of silencing PCs. Examination of feed-forward recruitment of MLIs by parallel fibres shows that during this P10/P14 time window, MLIs were more responsive to incoming excitatory drive. Thus, we conclude that IL1RAPL1 exerts a key function during cerebellar development in establishing local excitation/inhibition balance.

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