The AKT-mTOR signaling transduction pathway plays an important role in neurodevelopment and synaptic plasticity. mTOR is a serine/threonine kinase that modulates signals from multiple neurotransmitters and phosphorylates specific proteins to regulate protein synthesis and cytoskeletal organization. There is substantial evidence demonstrating abnormalities in AKT expression and activity in different schizophrenia (SZ) models. However, direct evidence for dysregulated mTOR kinase activity and its consequences on downstream effector proteins in SZ pathophysiology is lacking. Recently, we reported reduced phosphorylation of mTOR at an activating site and abnormal mTOR complex formation in the SZ dorsolateral prefrontal cortex (DLPFC). Here, we expand on our hypothesis of disrupted mTOR signaling in the SZ brain and studied the expression and activity of downstream effector proteins of mTOR complexes and the kinase activity profiles of SZ subjects. We found that S6RP phosphorylation, downstream of mTOR complex I, is reduced, whereas PKCα phosphorylation, downstream of mTOR complex II, is increased in SZ DLPFC. In rats chronically treated with haloperidol, we showed that S6RP phosphorylation is increased in the rat frontal cortex, suggesting a potential novel mechanism of action for antipsychotics. We also demonstrated key differences in kinase signaling networks between SZ and comparison subjects for both males and females using kinome peptide arrays. We further investigated the role of mTOR kinase activity by inhibiting it with rapamycin in postmortem tissue and compared the impact of mTOR inhibition in SZ and comparison subjects using kinome arrays. We found that SZ subjects are globally more sensitive to rapamycin treatment and AMP-activated protein kinase (AMPK) contributes to this differential kinase activity. Together, our findings provide new insights into the role of mTOR as a master regulator of kinase activity in SZ and suggest potential targets for therapeutic intervention.
Subscribe to Journal
Get full journal access for 1 year
only $33.25 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Owen MJ, Sawa A, Mortensen PB. Schizophrenia. Lancet. 2016;388:86–97.
Funk AJ, McCullumsmith RE, Haroutunian V, Meador-Woodruff JH. Abnormal Activity of the MAPK- and cAMP-Associated Signaling Pathways in Frontal Cortical Areas in Postmortem Brain in Schizophrenia. Neuropsychopharmacology. 2012;37:896–905.
Kyosseva SV, Elbein AD, Griffin WST, Mrak RE, Lyon M, Karson CN. Mitogen-activated protein kinases in schizophrenia. Biol. Psychiatry. 1999;46:689–96.
Emamian ES. AKT/GSK3 signaling pathway and schizophrenia. Front. Mol. Neurosci. 2012;5:33.
Emamian ES, Hall D, Birnbaum MJ, Karayiorgou M, Gogos JA. Convergent evidence for impaired AKT1-GSK3β signaling in schizophrenia. Nat. Genet. 2004;36:131–7.
McGuire JL, Hammond JH, Yates SD, Chen D, Haroutunian V, Meador-Woodruff JH, et al. Altered serine/threonine kinase activity in schizophrenia. Brain Res. 2014;1568:42–54.
Chadha, R & Meador-Woodruff, JH Downregulated AKT-mTOR signaling pathway proteins in dorsolateral prefrontal cortex in Schizophrenia. Neuropsychopharmacology 1–9 (2020) https://doi.org/10.1038/s41386-020-0614-2.
Wang L, Zhou K, Fu Z, Yu D, Huang H, Zang X, et al. Brain Development and Akt Signaling: the Crossroads of Signaling Pathway and Neurodevelopmental Diseases. J. Mol. Neurosci. 2017;61:379–84.
Costa-Mattioli M, Monteggia LM. mTOR complexes in neurodevelopmental and neuropsychiatric disorders. Nat. Neurosci. 2013;16:1537–43.
McGuire JL, Depasquale EA, Funk AJ, O’Donnovan SM, Hasselfeld K, Marwaha S, et al. Abnormalities of signal transduction networks in chronic schizophrenia. NPJ Schizophr. 2017;3:30.
Bentea E, Depasquale EAKK, O’donovan SM, Sullivan CR, Simmons M, Meador-Woodruff JH, et al. Kinase network dysregulation in a human induced pluripotent stem cell model of DISC1 schizophrenia. Mol. Omi. 2019;15:173–88.
Kozlovsky N, Shanon-Weickert C, Tomaskovic-Crook E, Kleinman JE, Belmaker RH, Agam G. Reduced GSK-3β mRNA levels in postmortem dorsolateral prefrontal cortex of schizophrenic patients. J. Neural Transm. 2004;111:1583–92.
Gong R, Park CS, Abbassi NR, Tang S-J. Roles of glutamate receptors and the mammalian target of rapamycin (mTOR) signaling pathway in activity-dependent dendritic protein synthesis in hippocampal neurons. J. Biol. Chem. 2006;281:18802–15.
Hsu W-L, Chung H-W, Wu C-Y, Wu H-I, Lee Y-T, Chen E-C, et al. Glutamate Stimulates Local Protein Synthesis in the Axons of Rat Cortical Neurons by Activating α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (AMPA) Receptors and Metabotropic Glutamate Receptors. J. Biol. Chem. 2015;290:20748–60.
English J, Fan Y, Föcking M, Lopez L, Hryniewiecka M, Wynne K, et al. Reduced protein synthesis in schizophrenia patient-derived olfactory cells. Transl. Psychiatry. 2015;5:e663.
Huang W, Zhu PJ, Zhang S, Zhou H, Stoica L, Galiano M, et al. mTORC2 controls actin polymerization required for consolidation of long-term memory. Nat. Neurosci. 2013;16:441–8.
Ibarra-Lecue I, Diez-Alarcia R, Morentin B, Meana JJ, Callado LF, Urigüen L. Ribosomal Protein S6 Hypofunction in Postmortem Human Brain Links mTORC1-Dependent Signaling and Schizophrenia. Front. Pharmacol. 2020;11:344.
Kim P, Scott MR, Meador-Woodruff JH. Abnormal expression of ER quality control and ER associated degradation proteins in the dorsolateral prefrontal cortex in schizophrenia. Schizophr. Res. 2018;197:484–91.
Kippe JM, Mueller TM, Haroutunian V, Meador-Woodruff JH. Abnormal N-acetylglucosaminyltransferase expression in prefrontal cortex in schizophrenia. Schizophr. Res. 2015;166:219–24.
Bauer DE, Haroutunian V, McCullumsmith RE, Meador-Woodruff JH. Expression of four housekeeping proteins in elderly patients with schizophrenia. J. Neural Transm. 2009;116:487–91.
Harte MK, Bachus SB, Reynolds GP. Increased N-acetylaspartate in rat striatum following long-term administration of haloperidol. Schizophr. Res. 2005;75:303–8.
Kashihara K, Sato M, Fujiwara Y, Harada T, Ogawa T, Otsuki S. Effects of intermittent and continuous haloperidol administration on the dopaminergic system in the rat brain. Biol. Psychiatry. 1986;21:650–6.
Bhambhvani HP, Mueller TM, Simmons MS, Meador-Woodruff JH. Actin polymerization is reduced in the anterior cingulate cortex of elderly patients with schizophrenia. Transl. Psychiatry. 2017;7:1278.
Dorsett CR, McGuire JL, Niedzielko TL, Depasquale EAK, Meller J, Floyd CL, et al. Traumatic brain injury induces alterations in cortical glutamate uptake without a reduction in glutamate transporter-1 protein expression. J. Neurotrauma. 2017;34:220–34.
DePasquale EAK, Alganem K, Bentea E, Nawreen N, McGuire JL, Naji F, et al. KRSA: Network-based Prediction of Differential Kinase Activity from Kinome Array Data. bioRxiv. 2020. https://doi.org/10.1101/2020.08.26.268581. 2020.08.26.268581
Xue Y, Liu Z, Gao X, Jin C, Wen L, Yao X, et al. GPS-SNO: Computational Prediction of Protein S-Nitrosylation Sites with a Modified GPS Algorithm. PLoS One. 2010;5:e11290.
Szklarczyk D, Morris JH, Cook H, Kuhn M, Wyder S, Simonovic M, et al. The STRING database in 2017: Quality-controlled protein-protein association networks, made broadly accessible. Nucleic Acids Res. 2017;45:D362–D368.
Biever A, Valjent E, Puighermanal E. Ribosomal protein S6 phosphorylation in the nervous system: From regulation to function. Front. Mol. Neurosci. 2015;8:75.
Hetman M, Slomnicki LP. Ribosomal biogenesis as an emerging target of neurodevelopmental pathologies. J. Neurochem. 2019;148:325–47.
Slomnicki LP, Pietrzak M, Vashishta A, Jones J, Lynch N, Elliot S, et al. Requirement of Neuronal Ribosome Synthesis for Growth and Maintenance of the Dendritic Tree. J. Biol. Chem. 2016;291:5721–39.
Bowling H, Zhang G, Bhattacharya A, Pérez-Cuesta LM, Deinhardt K, Hoeffer CA, et al. Antipsychotics activate mTORC1-dependent translation to enhance neuronal morphological complexity. Sci. Signal. 2014;7:ra4.
Valjent E, Bertran-Gonzalez J, Bowling H, Lopez S, Santini E, Matamales M, et al. Haloperidol regulates the state of phosphorylation of ribosomal protein S6 via activation of PKA and phosphorylation of DARPP-32. Neuropsychopharmacology. 2011;36:2561–70.
Bonito-Oliva A, Pallottino S, Bertran-Gonzalez J, Girault J-A, Valjent E, Fisone G. Haloperidol promotes mTORC1-dependent phosphorylation of ribosomal protein S6 via dopamine- and cAMP-regulated phosphoprotein of 32 kDa and inhibition of protein phosphatase-1. Neuropharmacology. 2013;72:197–203.
Pan B, Huang XF, Deng C. Aripiprazole and haloperidol activate GSK3β-dependent signalling pathway differentially in various brain regions of rats. Int. J. Mol. Sci. 2016;17:459.
Roh M-S, Seo MS, Kim Y, Kim SH, Jeon WJ, Ahn YM, et al. Haloperidol and clozapine differentially regulate signals upstream of glycogen synthase kinase 3 in the rat frontal cortex. Exp. Mol. Med. 2007;39:353–60.
Garza-Lombó C, Schroder A, Reyes-Reyes EM, Franco R. mTOR/AMPK signaling in the brain: Cell metabolism, proteostasis and survival. Current Opinion in Toxicology. 2018;8:102–10.
Gwinn DM, Shackelford DB, Egan DF, Mihaylova MM, Mery A, Vasquez DS, et al. AMPK Phosphorylation of Raptor Mediates a Metabolic Checkpoint. Mol. Cell. 2008;30:214–26.
Inoki K, Kim J, Guan K-L. AMPK and mTOR in Cellular Energy Homeostasis and Drug Targets. Annu. Rev. Pharmacol. Toxicol. 2012;52:381–400.
Rabanal-Ruiz Y, Otten EG, Korolchuk VI. MTORC1 as the main gateway to autophagy. Essays in Biochemistry. 2017;61:565–84.
Al Eissa MM, Fiorentino A, Sharp SI, O’Brien NL, Wolfe K, Giaroli G, et al. Exome sequence analysis and follow up genotyping implicates rare ULK1 variants to be involved in susceptibility to schizophrenia. Ann. Hum. Genet. 2018;82:88–92.
Barnes MR, Huxley-Jones J, Maycox PR, Lennon M, Thornber A, Kelly F, et al. Transcription and pathway analysis of the superior temporal cortex and anterior prefrontal cortex in schizophrenia. J. Neurosci. Res. 2011;89:1218–27.
Kroemer G, Mariño G, Levine B. Autophagy and the Integrated Stress Response. Molecular Cell. 2010;40:280–93.
Horesh Y, Katsel P, Haroutunian V, Domany E. Gene expression signature is shared by patients with Alzheimer’s disease and schizophrenia at the superior temporal gyrus. Eur. J. Neurol. 2011;18:410–24.
Glantz LA, Lewis DA. Decreased dendritic spine density on prefrontal cortical pyramidal neurons in schizophrenia. Arch. Gen. Psychiatry. 2000;57:65–73.
Glausier JR, Lewis DA. Dendritic spine pathology in schizophrenia. Neuroscience. 2013;251:90–107.
Garey LJ, Ong WY, Patel TS, Kanani M, Davis A, Mortimer AM, et al. Reduced dendritic spine density on cerebral cortical pyramidal neurons in schizophrenia. J. Neurol. Neurosurg. Psychiatry. 1998;65:446–53.
Lewis DA, Curley AA, Glausier JR, Volk DW. Cortical parvalbumin interneurons and cognitive dysfunction in schizophrenia. Trends in Neurosciences. 2012;35:57–67.
Rojas-Benítez D, Ibar C, Glavic Á. The Drosophila EKC/KEOPS complex: Roles in protein synthesis homeostasis and animal growth. Fly (Austin). 2013;7:168–72.
Wu MF, Wang SG. Human TAO kinase 1 induces apoptosis in SH-SY5Y cells. Cell Biol. Int. 2008;32:151–6.
Pinner AL, Tucholski J, Haroutunian V, McCullumsmith RE, Meador-Woodruff JH. Decreased protein S-palmitoylation in dorsolateral prefrontal cortex in schizophrenia. Schizophr. Res. 2016;177:78–87.
Mccullumsmith RE, Hammond JH, Shan D, Meador-Woodruff JH. Postmortem brain: An underutilized substrate for studying severe mental illness. Neuropsychopharmacology. 2014;39:65–87.
The authors would like to thank Dr. Rosalinda Roberts and the Alabama Brain Collection for postmortem cortical samples used in assay development for immunoblotting analyses.
RC was supported by the Marie and Emmett Carmichael fund for graduate students in biosciences. KA and REM were supported by NIMH R01 MH107487 and MH121102.
Conflict of interest
The authors declare no competing interests.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
Chadha, R., Alganem, K., Mccullumsmith, R.E. et al. mTOR kinase activity disrupts a phosphorylation signaling network in schizophrenia brain. Mol Psychiatry (2021). https://doi.org/10.1038/s41380-021-01135-9