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Nat Neurosci. 2016 Jul;19(7):926-934. doi: 10.1038/nn.4319. Epub 2016 Jun 6.

SHANK3 controls maturation of social reward circuits in the VTA.

Author information

1
Dept. of Fundamental Neurosciences, University of Lausanne, CH-1005, Lausanne, Switzerland.
2
Centre National de la Recherche Scientifique, Interdisciplinary Institute for Neuroscience, UMR 5297, Bordeaux, France.
3
Université de Bordeaux, Bordeaux, France.
4
Dept. of Basic Neurosciences, Medical Faculty, University of Geneva, CH-1211 Geneva, Switzerland.
5
Centre National de la Recherche Scientifique, Neurodegeneratives diseases Institute, UMR 5293, Bordeaux, France.
6
Clinic of Neurology, Geneva University Hospital, CH-1211 Geneva, Switzerland.
#
Contributed equally

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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PMID:
27273769
PMCID:
PMC4948673
DOI:
10.1038/nn.4319
[Indexed for MEDLINE]
Free PMC Article

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