Article | Published:

SHANK3 controls maturation of social reward circuits in the VTA

Nature Neuroscience volume 19, pages 926934 (2016) | Download Citation

Abstract

Haploinsufficiency of SHANK3, encoding the synapse scaffolding protein SHANK3, leads to a highly penetrant form of autism spectrum disorder. How SHANK3 insufficiency affects specific neural circuits and how this is related to specific symptoms remains elusive. Here we used shRNA to model Shank3 insufficiency in the ventral tegmental area of mice. We identified dopamine (DA) and GABA cell-type-specific changes in excitatory synapse transmission that converge to reduce DA neuron activity and generate behavioral deficits, including impaired social preference. Administration of a positive allosteric modulator of the type 1 metabotropic glutamate receptors mGluR1 during the first postnatal week restored DA neuron excitatory synapse transmission and partially rescued the social preference defects, while optogenetic DA neuron stimulation was sufficient to enhance social preference. Collectively, these data reveal the contribution of impaired ventral tegmental area function to social behaviors and identify mGluR1 modulation during postnatal development as a potential treatment strategy.

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Acknowledgements

We thank M. Mameli, D. Jabaudon and F. Gardoni for the critical reading of the manuscript. C.B is supported by the Swiss National Science Foundation, Pierre Mercier Foundation and NCCR Synapsy. C.L. is supported by the Swiss National Science Foundation and by the European Research Council (MeSSI Advanced grant). This work was supported by a grant from the Simons Foundation (SFARI #239496 to C.L.).

Author information

Author notes

    • Sebastiano Bariselli
    •  & Stamatina Tzanoulinou

    These authors contributed equally to this work.

Affiliations

  1. Department of Fundamental Neurosciences, University of Lausanne, Lausanne, Switzerland.

    • Sebastiano Bariselli
    • , Stamatina Tzanoulinou
    • , Christelle Glangetas
    • , Clément Prévost-Solié
    • , Luca Pucci
    • , Paola Bezzi
    •  & Camilla Bellone
  2. Centre National de la Recherche Scientifique, Interdisciplinary Institute for Neuroscience, Bordeaux, France.

    • Christelle Glangetas
    •  & François Georges
  3. Université de Bordeaux, Bordeaux, France.

    • Christelle Glangetas
    •  & François Georges
  4. Department of Basic Neurosciences, Medical Faculty, University of Geneva, Geneva, Switzerland.

    • Joanna Viguié
    • , Eoin C O'Connor
    •  & Christian Lüscher
  5. Centre National de la Recherche Scientifique, Neurodegenerative Diseases Institute, Bordeaux, France.

    • François Georges
  6. Clinic of Neurology, Geneva University Hospital, Geneva, Switzerland.

    • Christian Lüscher

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Contributions

All VTA SHANK3 infections were performed by S.B. In vitro electrophysiology experiments were performed by S.B. Behavioral experiments were performed by S.T., with assistance from C.P.-S., S.B. and E.C.O'C. S.B. and S.T. performed the statistical analyses for the in vitro electrophysiology and the behavioral experiments, and contributed to the statistical analysis of the in vivo electrophysiology experiments. In vivo recordings were performed by C.G. and F.G. Immunohistochemistry was performed by S.B., J.V. and C.G. Western blots were performed by L.P. and P.B. The study was designed and the manuscript written by C.B., with assistance from S.B., E.C.O., C.L. and F.G.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Camilla Bellone.

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DOI

https://doi.org/10.1038/nn.4319

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