Abstract
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.
Highlights
Bipolar disorder (BD), characterized by recurrent mood swings between depression and mania, is a highly heritable and chronic mental illness that affects approximately 2.5% of the population worldwide (Merikangas et al, 2011)
We found that several biological pathways including ‘‘mammalian target of rapamycin complex 1 (mTORC1) signaling’’, ‘‘protein secretion’’, ‘‘Myc targets V1’’, ‘‘unfolded protein response (UPR)’’, and ‘‘oxidative phosphorylation’’ were represented by the genes up-regulated in SH3 and multiple ankyrin repeat domains 3 (Shank3) TG striatum (Figure 1C and Supplementary Table S4)
Based on the RNA-seq analysis, we examined mTORC1 activity and found that it was decreased in the striatum of Shank3 TG mice
Summary
Bipolar disorder (BD), characterized by recurrent mood swings between depression and mania, is a highly heritable and chronic mental illness that affects approximately 2.5% of the population worldwide (Merikangas et al, 2011). Manic episodes are the defining feature of BD, and manic symptoms include hyperactivity, impulsivity, elevated mood, reduced anxiety and decreased need for sleep (Grande et al, 2016). These core symptoms suggest that a dysfunction of the striatum, the key component of the brain motor and reward systems, may be involved in the pathogenesis of manic disorder. Ras homolog enriched in striatum (Rhes, encoded by Rasd gene), a small GTPase highly enriched in the striatal medium spiny neurons (MSNs), has roles similar to Rheb in directly binding and activating mTORC1 in a GTP-dependent manner (Subramaniam et al, 2011). The activity of Rhes is regulated by Ras guanyl releasing protein 1 (RasGRP1), a guanine nucleotide exchange factor (GEF), in the striatum (Shahani et al, 2016)
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