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In utero exposure to cocaine delays postnatal synaptic maturation of glutamatergic transmission in the VTA

Nature Neuroscience volume 14, pages 14391446 (2011) | Download Citation

Abstract

Maternal exposure to cocaine may perturb fetal development and affect synaptic maturation in the offspring. However, the molecular mechanism underlying such changes remains elusive. We focused on the postnatal maturation of glutamatergic transmission onto ventral tegmental area dopamine neurons in the mouse. We found that, during the first postnatal week, transmission was dominated by calcium-permeable AMPA receptors and GluN2B-containing NMDA receptors. Subsequently, mGluR1 receptors drove synaptic insertion of calcium-impermeable AMPA receptors and GluN2A-containing NMDAR. When pregnant mice were exposed to cocaine, this glutamate receptor switch was delayed in offspring as a result of a direct effect of cocaine on the fetal dopamine transporter and impaired mGluR1 function. Finally, positive modulation of mGluR1 in vivo was sufficient to rescue maturation. These data identify the molecular target through which in utero cocaine delays postnatal synaptic maturation, reveal the underlying expression mechanism of this impairment and propose a potential rescue strategy.

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Acknowledgements

We thank members of the Lüscher laboratory M. Serafin and A. Holtmaat for critical reading of the manuscript. We thank H.H. Gu, who provided the DAT knock-in mouse line, and K. Huber, who provided the breeding pairs for the mGluR1 mutant mouse line. C.B. is an Ambizione fellow. This work was supported by the Swiss National Science Foundation.

Author information

Author notes

    • Manuel Mameli

    Present address: Institut du Fer à Moulin, Paris, France.

Affiliations

  1. Department of Basic Neurosciences, Medical Faculty, University of Geneva, Geneva, Switzerland.

    • Camilla Bellone
    • , Manuel Mameli
    •  & Christian Lüscher
  2. Clinic of Neurology, Department of Clinical Neurosciences, Geneva University Hospital, Geneva, Switzerland.

    • Christian Lüscher

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Contributions

C.B. carried out the in vitro electrophysiology experiments with the help of M.M., who performed the imaging experiments. C.L. designed the study and wrote the manuscript with the help of the other authors.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Camilla Bellone or Christian Lüscher.

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DOI

https://doi.org/10.1038/nn.2930

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