SHANK3 controls maturation of social reward circuits in the VTA.
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.
Dept. of Fundamental Neurosciences, University of Lausanne, CH-1005, Lausanne, Switzerland.
Sebastiano
S
Bariselli
Dept. of Fundamental Neurosciences, University of Lausanne, CH-1005, Lausanne, Switzerland.
Stamatina
S
Tzanoulinou
Dept. of Fundamental Neurosciences, University of Lausanne, CH-1005, Lausanne, Switzerland.|Centre National de la Recherche Scientifique, Interdisciplinary Institute for Neuroscience, UMR 5297, Bordeaux, France.|Université de Bordeaux, Bordeaux, France.
Christelle
C
Glangetas
Dept. of Fundamental Neurosciences, University of Lausanne, CH-1005, Lausanne, Switzerland.
Clément
C
Prévost-Solié
Dept. of Fundamental Neurosciences, University of Lausanne, CH-1005, Lausanne, Switzerland.
Luca
L
Pucci
Dept. of Basic Neurosciences, Medical Faculty, University of Geneva, CH-1211 Geneva, Switzerland.
Joanna
J
Viguié
Dept. of Fundamental Neurosciences, University of Lausanne, CH-1005, Lausanne, Switzerland.
Paola
P
Bezzi
Dept. of Basic Neurosciences, Medical Faculty, University of Geneva, CH-1211 Geneva, Switzerland.
Eoin C
EC
O'Connor
Centre National de la Recherche Scientifique, Interdisciplinary Institute for Neuroscience, UMR 5297, Bordeaux, France.|Université de Bordeaux, Bordeaux, France.|Centre National de la Recherche Scientifique, Neurodegeneratives diseases Institute, UMR 5293, Bordeaux, France.
François
F
Georges
Dept. of Basic Neurosciences, Medical Faculty, University of Geneva, CH-1211 Geneva, Switzerland.|Clinic of Neurology, Geneva University Hospital, CH-1211 Geneva, Switzerland.
Christian
C
Lüscher
Dept. of Fundamental Neurosciences, University of Lausanne, CH-1005, Lausanne, Switzerland.
Camilla
C
Bellone
D000818:Animals; D000067877:Autism Spectrum Disorder / Q000378:metabolism; D001522:Behavior, Animal / Q000502:physiology*; D004298:Dopamine / Q000378:metabolism; D059290:Dopaminergic Neurons / Q000378:metabolism*; D059330:GABAergic Neurons / Q000187:drug effects; D006624:Hippocampus / Q000378:metabolism*; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008840:Microfilament Proteins; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D018408:Patch-Clamp Techniques / Q000379:methods; D012201:Reward; D013569:Synapses / Q000378:metabolism; D009435:Synaptic Transmission / Q000502:physiology; D017557:Ventral Tegmental Area / Q000378:metabolism*
D008840:Microfilament Proteins; D009419:Nerve Tissue Proteins; C492356:Shank3 protein, mouse; D004298:Dopamine