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

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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Figure 1: Developmental expression of glutamate receptors in DA neurons.
Figure 2: AMPA receptors in DA neurons mediate calcium influx during postnatal development.
Figure 3: Glutamate receptors maturation in mGluR1−/− mice.
Figure 4: mGluR1s control synaptic maturation of AMPA and NMDA receptors.
Figure 5: In utero cocaine exposure impairs synaptic maturation.
Figure 6: Cocaine-evoked plasticity and postnatal maturation of AMPARs in DAT-KI mice.
Figure 7: Dopamine modulation of mGluR1.
Figure 8: mGluR1 rescues of cocaine-induced impairment of synaptic maturation.

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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.

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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.

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Correspondence to Camilla Bellone or Christian Lüscher.

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The authors declare no competing financial interests.

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Bellone, C., Mameli, M. & Lüscher, C. In utero exposure to cocaine delays postnatal synaptic maturation of glutamatergic transmission in the VTA. Nat Neurosci 14, 1439–1446 (2011). https://doi.org/10.1038/nn.2930

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