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.

SHANK3 controls maturation of social reward circuits in the VTA / Bariselli, S.; Tzanoulinou, S.; Glangetas, C.; Prevost-Solie, C.; Pucci, L.; Viguie, J.; Bezzi, P.; O'Connor, E. C.; Georges, F.; Luscher, C.; Bellone, C.. - In: NATURE NEUROSCIENCE. - ISSN 1097-6256. - 19:7(2016), pp. 926-934. [10.1038/nn.4319]

SHANK3 controls maturation of social reward circuits in the VTA

Bezzi P.
Membro del Collaboration Group
;
2016

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.
2016
animals; autism spectrum disorder; behavior, animal; dopamine; dopaminergic neurons; gabaergic neurons; hippocampus; inhibitory postsynaptic potentials; mice, inbred c57bl; mice, transgenic; nerve tissue proteins; patch-clamp techniques; synapses; synaptic transmission; ventral tegmental area; reward
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SHANK3 controls maturation of social reward circuits in the VTA / Bariselli, S.; Tzanoulinou, S.; Glangetas, C.; Prevost-Solie, C.; Pucci, L.; Viguie, J.; Bezzi, P.; O'Connor, E. C.; Georges, F.; Luscher, C.; Bellone, C.. - In: NATURE NEUROSCIENCE. - ISSN 1097-6256. - 19:7(2016), pp. 926-934. [10.1038/nn.4319]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/1405188
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