Mania causes symptoms of hyperactivity, impulsivity, elevated mood, reduced anxiety and decreased need for sleep, which suggests that the dysfunction of the striatum, a critical component of the brain motor and reward system, can be causally associated with
mania. However, detailed molecular pathophysiology underlying the striatal dysfunction in
mania remains largely unknown. In this study, we aimed to identify the molecular pathways showing alterations in the striatum of SH3 and multiple ankyrin repeat domains 3 (Shank3)-overexpressing transgenic (TG) mice that display manic-like behaviors. The results of transcriptome analysis suggested that
mammalian target of rapamycin complex 1 (
mTORC1) signaling may be the primary molecular signature altered in the Shank3 TG striatum. Indeed, we found that striatal
mTORC1 activity, as measured by mTOR S2448 phosphorylation, was significantly decreased in the Shank3 TG mice compared to wild-type (WT) mice. To elucidate the potential underlying mechanism, we re-analyzed previously reported
protein interactomes, and detected a high connectivity between Shank3 and several upstream regulators of
mTORC1, such as
tuberous sclerosis 1 (TSC1), TSC2 and Ras homolog enriched in striatum (Rhes), via 94 common interactors that we denominated "Shank3-
mTORC1 interactome". We noticed that, among the 94 common interactors, 11
proteins were related to actin filaments, the level of which was increased in the dorsal striatum of Shank3 TG mice. Furthermore, we could co-immunoprecipitate Shank3, Rhes and
Wiskott-Aldrich syndrome protein family verprolin-homologous
protein 1 (WAVE1)
proteins from the striatal lysate of Shank3 TG mice. By comparing with the gene sets of
psychiatric disorders, we also observed that the 94
proteins of Shank3-mTORC1 interactome were significantly associated with
bipolar disorder (BD). Altogether, our results suggest a
protein interaction-mediated connectivity between Shank3 and certain upstream regulators of
mTORC1 that might contribute to the abnormal striatal
mTORC1 activity and to the manic-like behaviors of Shank3 TG mice.