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Abnormal wiring of CCK+ basket cells disrupts spatial information coding

Nature Neuroscience volume 20, pages 784792 (2017) | Download Citation

Abstract

The function of cortical GABAergic interneurons is largely determined by their integration into specific neural circuits, but the mechanisms controlling the wiring of these cells remain largely unknown. This is particularly true for a major population of basket cells that express the neuropeptide cholecystokinin (CCK). Here we found that the tyrosine kinase receptor ErbB4 was required for the normal integration into cortical circuits of basket cells expressing CCK and vesicular glutamate transporter 3 (VGlut3). The number of inhibitory synapses made by CCK+VGlut3+ basket cells and the inhibitory drive they exerted on pyramidal cells were reduced in conditional mice lacking ErbB4. Developmental disruption of the connectivity of these cells diminished the power of theta oscillations during exploratory behavior, disrupted spatial coding by place cells, and caused selective alterations in spatial learning and memory in adult mice. These results suggest that normal integration of CCK+ basket cells in cortical networks is key to support spatial coding in the hippocampus.

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Acknowledgements

We are very thankful to C. Garcia-Frigola for scientific advice and support, M. Fernández, D. Baeza and V. Rodríguez-Millán for technical assistance, T. Gil and F. Navarrete for lab support, and J.Z. Huang (Cold Spring Harbor Laboratory) for mouse colonies (Cck-Cre and VIP-Cre). We thank C. Fernandes for guidance during an early phase of behavioral experiments at King's College London, S. Al Abed for technical advice and stimulating discussions on behavioral experiments performed at the Magendie Institute, and C. Leteneur for help with the behavioral experiments. We are grateful to L. Menéndez de la Prida and M. Maravall for critically reading early versions of this manuscript, and members of the Marín and Rico laboratories for stimulating discussions and ideas. Supported by grants from Fundación Alicia Koplowitz and the European Research Council (ERC-2012-StG 310021) to B.R., from the European Research Council (ERC-2011-AdG 293683) to O.M., from the Spanish Government (CONSOLIDER CSD2007-00023) and Lilly Research Awards Program to B.R. and O.M, and from the French government (ANR-10-EQX-008-1 to A.M. and LabEX BRAIN ANR-10-LABX-43 to A.F. and A.M.). O.M. and B.R. are Wellcome Trust Investigators.

Author information

Author notes

    • Isabel del Pino
    •  & Jorge R Brotons-Mas

    These authors contributed equally to this work.

    • Oscar Marín
    •  & Beatriz Rico

    These authors jointly directed this work.

Affiliations

  1. Centre for Developmental Neurobiology, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.

    • Isabel del Pino
    • , André Marques-Smith
    • , Oscar Marín
    •  & Beatriz Rico
  2. Instituto de Neurociencias, Consejo Superior de Investigaciones Científicas & Universidad Miguel Hernández, Sant Joan d'Alacant, Spain.

    • Isabel del Pino
    • , Jorge R Brotons-Mas
    • , Oscar Marín
    •  & Beatriz Rico
  3. Neurocentre Magendie INSERM U1215, Bordeaux, France.

    • Isabel del Pino
    • , Aline Marighetto
    •  & Andreas Frick
  4. MRC Centre for Neurodevelopmental Disorders, King's College London, London, UK.

    • André Marques-Smith
    • , Oscar Marín
    •  & Beatriz Rico

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Contributions

I.d.P. performed cell, synaptic, biochemical and behavior experiments and analyzed data. J.R.B.-M. performed in vivo electrophysiology recordings and analyzed data. A.M.-S. carried out in vitro electrophysiology recordings and analyzed data. A.M. contributed to the behavior analysis. A.F. contribute with resources. I.d.P., O.M. and B.R. wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Oscar Marín or Beatriz Rico.

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DOI

https://doi.org/10.1038/nn.4544

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