Several mutations within SHANK3 gene have been identified in Autism Spectrum Disorder patients and several studies have now started to show that those mutations could impact different brain circuits leading to the heterogeneity of the disease. Here we show that, compared to a mouse model lacking SHANK3 proline-rich containing isoforms, in a mouse model lacking SHANK3 ANK(yrin)-domain containing isoforms, the excitatory synaptic transmission within the Ventral Tegmental Area is not affected. We discuss about the possibility that different domains of SHANK3 are involved in regulating the synapses in a circuit-specific manner resulting in different behavioral and synaptic phenotypes.