DOI: 10.14704/nq.2017.15.4.1121

The Depression/Schizophrenia Continuum: Does Cytoskeletal Tensegrity Play a Role?

John Gardiner


There is mounting evidence that schizophrenia and depression are polar extremes of the same processes. The neuronal microtubule cytoskeleton is regulated through the actions of microtubule-associated proteins, the centrosome, tubulin posttranslational modifications and differential expression of tubulin isoforms. It is beginning to be thought that they may be important in the development of consciousness itself. It is proposed here that cytoskeletal tensegrity architecture plays a pivotal role in the etiology of psychiatric conditions. If the subcellular architecture is too tense, schizophrenia, if to loose, depression. This review focuses on the role of the microtubule cytoskeleton in schizophrenia, bipolar disorder and depression. Schizophrenia appears to be a disorder of microtubule architecture, depression one of intracellular transport along microtubules and bipolar disorder shares aspects of both schizophrenia and depression. Both current and potential treatments for these disorders target the microtubule cytoskeleton.

Full Text:



Alomari MA, Khabour OF, Alzoubi KH, Alzubi MA. Forced and voluntary exercises equally improve spatial learning and memory and hippocampal BDNF levels. Behavioural Brain Research 2013;247:34-39.

Altamura AC, Buoli M, Caldiroli A, Caron L, Melter CC, Dobrea C, Cigliobianco M, Quarantini FZ. Misdiagnosis, duration of untreated illness (DUI) and outcome in bipolar patients with psychotic symptoms: a naturalistic study. Journal of Affective Disorders 2015;182:70-5.

Arnold SE, Lee VM, Gur RE, Trojanowski JQ. Abnormal expression of two microtubule-associated proteins (MAP2 and MAP5) in specific subfields of the hippocampal formation in schizophrenia. Proceedings of the National Academy of Sciences 1991;88(23):10850-4.

Benitez-King G, Ramirez-Rodriguez G, Ortiz-López L. Altered microtubule associated proteins in schizophrenia. NeuroQuantology 2007;5(1): 58-61.

Bianchi M, Hagan JJ, Heidbreder CA. Neuronal plasticity, stress and depression: involvement of the cytoskeletal microtubular system?. Current Drug Targets-CNS and Neurologıcal Dısorders 2005;4(5):597-611.

Bianchi M, Baulieu EE. 3β-Methoxy-pregnenolone (MAP4343) as an innovative therapeutic approach for depressive disorders. Proceedings of the National Academy of Sciences 2012;109(5):1713-8.

Boukhris T, Sheehy O, Mottron L, Bérard A. Antidepressant use during pregnancy and the risk of autism spectrum disorder in children. JAMA pediatrics 2016;170(2):117-24.

Boydell J, Van Os J, McKenzie K, Allardyce J, Goel R, McCreadie RG, Murray RM. Incidence of schizophrenia in ethnic minorities in London: ecological study into interactions with environment. BMJ 2001;323(7325):1336.

Breland JY, Mignogna J, Kiefer L, Marsh L. Models for treating depression in specialty medical settings: a narrative review. General hospital Psychiatry 2015;37(4):315-322.

Castrén E, Rantamäki T. The role of BDNF and its receptors in depression and antidepressant drug action: reactivation of developmental plasticity. Developmental Neurobiology 2010;70(5):289-97.

Craddock TJ, Tuszynski JA, Hameroff S. Cytoskeletal signaling: is memory encoded in microtubule lattices by CaMKII phosphorylation?. PLoS Computational Biology 2012;8(3):e1002421.

Creppe C, Malinouskaya L, Volvert ML, Gillard M, Close P, Malaise O, Laguesse S, Cornez I, Rahmouni S, Ormenese S, Belachew S. Elongator controls the migration and differentiation of cortical neurons through acetylation of α-tubulin. Cell 2009;136(3):551-564.

Crespi F. Further electrochemical and behavioural evidence of a direct relationship between central 5-HT and cytoskeleton in the control of mood. The Open Neurology Journal 2010;4:5-14.

Cui DH, Jiang KD, Jiang SD, Xu YF, Yao H. The tumor suppressor adenomatous polyposis coli gene is associated with susceptibility to schizophrenia. Molecular Psychiatry 2005 ;10(7):669-77.

Dailly E, Chenu F, Renard CE, Bourin M. Dopamine, depression and antidepressants. Fundamental & Clinical Pharmacology 2004;18(6):601-7.

Didonna A, Opal P. The promise and perils of HDAC inhibitors in neurodegeneration. Annals of Clinical and Translational Neurology 2015;2(1):79-101.

Du J, Wei Y, Liu L, Wang Y, Khairova R, Blumenthal R, Tragon T, Hunsberger JG, Machado-Vieira R, Drevets W, Wang YT. A kinesin signaling complex mediates the ability of GSK-3β to affect mood-associated behaviors. Proceedings of the National Academy of Sciences 2010;107(25):11573-8.

Dunlop DD, Song J, Lyons JS, Manheim LM, Chang RW. Racial/ethnic differences in rates of depression among preretirement adults. American Journal of Public Health 2003;93(11):1945-52.

Eggers AE. A serotonin hypothesis of schizophrenia. Medical Hypotheses 2013;80(6):791-4.

Emerson DJ, Weiser BP, Psonis J, Liao Z, Taratula O, Fiamengo A, Wang X, Sugasawa K, Smith III AB, Eckenhoff RG, Dmochowski IJ. Direct modulation of microtubule stability contributes to anthracene general anesthesia. Journal of the American Chemical Society 2013;135(14):5389-98.

Evins AE, Cather C, Laffer A. Treatment of tobacco use disorders in smokers with serious mental illness: toward clinical best practices. Harvard Review of Psychiatry 2015;23(2):90-98.

Fallin MD, Lasseter VK, Avramopoulos D, Nicodemus KK, Wolyniec PS, McGrath JA, Steel G, Nestadt G, Liang KY, Huganir RL, Valle D. Bipolar I disorder and schizophrenia: a 440–single-nucleotide polymorphism screen of 64 candidate genes among Ashkenazi Jewish case-parent trios. The American Journal of Human Genetics 2005;77(6):918-36.

Ganguly A, Yang H, Cabral F. Class III β-tubulin counteracts the ability of paclitaxel to inhibit cell migration. Oncotarget 2011;2(5):368-77.

Gardiner J, Marc J, Overall R. Cytoskeletal thermal ratchets and cytoskeletal tensegrity: determinants of brain asymmetry and symmetry?. Frontiers in Bioscience: A Journal and Virtual Library 2008;13:464-6.

George D, Gálvez V, Martin D, Kumar D, Leyden J, Hadzi-Pavlovic D, Harper S, Brodaty H, Glue P, Taylor R, Mitchell PB. Pilot Randomized-Controlled Trial of Titrated Subcutaneous Ketamine in Older Patients with Treatment Resistant Depression. The American Journal of Geriatric Psychiatry 2017;25(11): 1199-1209.

Goldberg JF, Truman CJ. Antidepressant‐induced mania: an overview of current controversies. Bipolar Disorders 2003;5(6):407-20.

Gozes I. Microtubules, schizophrenia and cognitive behavior: preclinical development of davunetide (NAP) as a peptide-drug candidate. Peptides 2011;32(2):428-31.

Grande I, Fries GR, Kunz M, Kapczinski F. The role of BDNF as a mediator of neuroplasticity in bipolar disorder. Psychiatry İnvestigation 2010;7(4):243-50..

Gürel G, Gustafson MA, Pepper JS, Horvitz HR, Koelle MR. Receptors and other signaling proteins required for serotonin control of locomotion in Caenorhabditis elegans. Genetics 2012;192(4):1359-71.

Ha TH, Yoon U, Lee KJ, Shin YW, Lee JM, Kim IY, Ha KS, Kim SI, Kwon JS. Fractal dimension of cerebral cortical surface in schizophrenia and obsessive–compulsive disorder. Neuroscience Letters 2005;384(1):172-76.

Hameroff S, Penrose R. Conscious events as orchestrated space-time selections. NeuroQuantology 2003;1(1): 10-35.

Hong M, Chen DC, Klein PS, Lee VM. Lithium reduces tau phosphorylation by inhibition of glycogen synthase kinase-3. Journal of Biological Chemistry 1997;272(40):25326-25332.

Hubbert C, Guardiola A, Shao R, Kawaguchi Y, Ito A, Nixon A, Yoshida M, Wang XF, Yao TP. HDAC6 is a microtubule-associated deacetylase. Nature 2002;417(6887):455-458.

Ingber DE, Wang N, Stamenović D. Tensegrity, cellular biophysics, and the mechanics of living systems. Reports on Progress in Physics 2014;77(4):046603.

Insolera R, Shao W, Airik R, Hildebrandt F, Shi SH. SDCCAG8 regulates pericentriolar material recruitment and neuronal migration in the developing cortex. Neuron 2014;83(4):805-822.

Ishizuka K, Kamiya A, Oh EC, Kanki H, Seshadri S, Robinson JF, Murdoch H, Dunlop AJ, Kubo KI, Furukori K, Huang B. DISC1-dependent switch from progenitor proliferation to migration in the developing cortex. Nature 2011; 473(7345): 92-6.

Janke C, Bulinski JC. Post-translational regulation of the microtubule cytoskeleton: mechanisms and functions. Nature Reviews Molecular Cell Biology 2011;12(12):773-86.

Jochems J, Boulden J, Lee BG, Blendy JA, Jarpe M, Mazitschek R, Van Duzer JH, Jones S, Berton O. Antidepressant-like properties of novel HDAC6-selective inhibitors with improved brain bioavailability. Neuropsychopharmacology 2014; 39(2):389-400.

Jones CA, Watson DJ, Fone KC. Animal models of schizophrenia. British Journal of Pharmacology 2011;164(4):1162-94.

Kellner Y, Gödecke N, Dierkes T, Thieme N, Zagrebelsky M, Korte M. The BDNF effects on dendritic spines of mature hippocampal neurons depend on neuronal activity. Frontiers in Synaptic Neuroscience 2014; 6: 5.

Kimura H, Tsuboi D, Wang C, Kushima I, Koide T, Ikeda M, Iwayama Y, Toyota T, Yamamoto N, Kunimoto S, Nakamura Y. Identification of rare, single-nucleotide mutations in NDE1 and their contributions to schizophrenia susceptibility. Schizophrenia Bulletin 2014; 41(3):744-53.

Kollman JM, Polka JK, Zelter A, Davis TN, Agard DA. Microtubule nucleating [ggr]-TuSC assembles structures with 13-fold microtubule-like symmetry. Nature 2010; 466(7308):879-82.

Kornfield, J, Fronsdal, G. Teachings of the Buddha. London: Shambhala, 2007.

Lally J, MacCabe JH. Antipsychotic medication in schizophrenia: a review. British Medical Bulletin 2015; 114(1):169-79.

Lang B, Pu J, Hunter I, Liu M, Martin-Granados C, Reilly TJ, Gao GD, Guan ZL, Li WD, Shi YY, He G. Recurrent deletions of ULK4 in schizophrenia: a gene crucial for neuritogenesis and neuronal motility. Journal of Cell Science 2014;127(3):630-640.

Law AJ, Hutchinson LJ, Burnet PW, Harrison PJ. Antipsychotics increase microtubule‐associated protein 2 mRNA but not spinophilin mRNA in rat hippocampus and cortex. Journal of Neuroscience Research 2004; 76(3): 376-82.

Lee HH, Jan LY, Jan YN. Drosophila IKK-related kinase Ik2 and Katanin p60-like 1 regulate dendrite pruning of sensory neuron during metamorphosis. Proceedings of the National Academy of Sciences 2009;106(15):6363-8.

Liu XH, Geng Z, Yan J, Li T, Chen Q, Zhang QY, Chen ZY. Blocking GSK3β-mediated dynamin1 phosphorylation enhances BDNF-dependent TrkB endocytosis and the protective effects of BDNF in neuronal and mouse models of Alzheimer's disease. Neurobiology of Disease 2015;74:377-91.

Mandelkow E, Mandelkow EM. Microtubules and microtubule-associated proteins. Current Opinion in Cell Biology 1995;7(1):72-81.

Millar JK, Christie S, Anderson S, Lawson D, Loh DH, Devon RS, Arveiler B, Muir WJ, Blackwood DH, Porteous DJ. Genomic structure and localisation within a linkage hotspot of Disrupted In Schizophrenia 1, a gene disrupted by a translocation segregating with schizophrenia. Molecular Psychiatry 2001;6(2):173-8.

Miñana MD, Montoliu C, Llansola M, Grisolı́a S, Felipo V. Nicotine prevents glutamate-induced proteolysis of the microtubule-associated protein MAP-2 and glutamate neurotoxicity in primary cultures of cerebellar neurons. Neuropharmacology 1998;37(7):847-57.

Mitchison T, Kirschner M. Dynamic instability of microtubule growth. Nature 1984;312(5991):237-42.

Moehle MS, Luduena RF, Haroutunian V, Meador-Woodruff JH, McCullumsmith RE. Regional differences in expression of β-tubulin isoforms in schizophrenia. Schizophrenia Research 2012;135(1):181-6.

Muñoz‐Estrada J, Benítez‐King G, Berlanga C, Meza I. Altered Subcellular Distribution of the 75‐kDa DISC1 Isoform, cAMP Accumulation, and Decreased Neuronal Migration in Schizophrenia and Bipolar Disorder: Implications for Neurodevelopment. CNS Neuroscience & Therapeutics 2015;21(5):446-53.

Narayanan S, Arthanari H, Wolfe MS, Wagner G. Molecular characterization of disrupted in schizophrenia-1 risk variant S704C reveals the formation of altered oligomeric assembly. Journal of Biological Chemistry 2011;286(51):44266-76.

Nieto R, Kukuljan M, Silva H. BDNF and schizophrenia: from neurodevelopment to neuronal plasticity, learning, and memory. Frontiers in Psychiatry 2013;49(45):1-11.

North BJ, Marshall BL, Borra MT, Denu JM, Verdin E. The human Sir2 ortholog, SIRT2, is an NAD+-dependent tubulin deacetylase. Molecular Cell 2003;11(2):437-44.

Pareyson D, Saveri P, Sagnelli A, Piscosquito G. Mitochondrial dynamics and inherited peripheral nerve diseases. Neuroscience Letters 2015;596:66-77.

Post RM. Role of BDNF in bipolar and unipolar disorder: clinical and theoretical implications. Journal of Psychiatric Research 2007;41(12):979-990.

Prota AE, Magiera MM, Kuijpers M, Bargsten K, Frey D, Wieser M, Jaussi R, Hoogenraad CC, Kammerer RA, Janke C, Steinmetz MO. Structural basis of tubulin tyrosination by tubulin tyrosine ligase. Journal of Cell Biololgy 2013;200(3):259-70.

Reed NA, Cai D, Blasius TL, Jih GT, Meyhofer E, Gaertig J, Verhey KJ. Microtubule acetylation promotes kinesin-1 binding and transport. Current Biology 2006;16(21):2166-2172.

Reimers JR, McKemmish LK, McKenzie RH, Mark AE, Hush NS. The revised Penrose–Hameroff orchestrated objective-reduction proposal for human consciousness is not scientifically justified: Comment on “Consciousness in the universe: a review of the ‘Orch OR’theory” by Hameroff and Penrose. Physics of Life Reviews 2014;11(1):101-3.

Sahu S, Ghosh S, Ghosh B, Aswani K, Hirata K, Fujita D, Bandyopadhyay A. Atomic water channel controlling remarkable properties of a single brain microtubule: correlating single protein to its supramolecular assembly. Biosensors and Bioelectronics 2013;47:141-8.

Schwartz RC, Blankenship DM. Racial disparities in psychotic disorder diagnosis: A review of empirical literature. World journal of Psychiatry 2014;4(4):133-40.

Shelton MA, Newman JT, Gu H, Sampson AR, Fish KN, MacDonald ML, Moyer CE, DiBitetto JV, Dorph-Petersen KA, Penzes P, Lewis DA. Loss of microtubule-associated protein 2 immunoreactivity linked to dendritic spine loss in schizophrenia. Biological Psychiatry 2015;78(6):374-85.

Södersten K, Pålsson E, Ishima T, Funa K, Landén M, Hashimoto K, Ågren H. Abnormality in serum levels of mature brain-derived neurotrophic factor (BDNF) and its precursor proBDNF in mood-stabilized patients with bipolar disorder: a study of two independent cohorts. Journal of Affective Disorders 2014;160:1-9.

Solis-Chagoyan H, Calixto E, Figueroa A, Montano LM, Berlanga C, Rodriguez-Verdugo MS, Romo F, Jiménez M, Gurrola CZ, Riquelme A, Benítez-King G. Microtubule organization and L-type voltage-activated calcium current in olfactory neuronal cells obtained from patients with schizophrenia and bipolar disorder. Schizophrenia Research 2013;143(2):384-9.

Sun MK, Nelson TJ, Alkon DL. Towards universal therapeutics for memory disorders. Trends in Pharmacological Sciences 2015;36(6):384-94.

Szyk A, Deaconescu AM, Piszczek G, Roll-Mecak A. Tubulin tyrosine ligase structure reveals adaptation of an ancient fold to bind and modify tubulin. Nature Structural & Molecular Biology 2011;18(11):1250-8.

Szyk A, Deaconescu AM, Spector J, Goodman B, Valenstein ML, Ziolkowska NE, Kormendi V, Grigorieff N, Roll-Mecak A. Molecular basis for age-dependent microtubule acetylation by tubulin acetyltransferase. Cell 2014;157(6):1405-15.

Takahashi M, Yamagiwa A, Nishimura T, Mukai H, Ono Y. Centrosomal proteins CG-NAP and kendrin provide microtubule nucleation sites by anchoring γ-tubulin ring complex. Molecular Biology of the Cell 2002;13(9):3235-45.

Tomppo L, Hennah W, Miettunen J, Järvelin MR, Veijola J, Ripatti S, Lahermo P, Lichtermann D, Peltonen L, Ekelund J. Association of variants in DISC1 with psychosis-related traits in a large population cohort. Archives of General Psychiatry 2009;66(2):134-41.

Van Woerkom AE. The major hallucinogens and the central cytoskeleton: an association beyond coincidence? Towards sub-cellular mechanisms in schizophrenia. Medical Hypotheses 1990;31(1):7-15.

Vasudevan KK, Jiang YY, Lechtreck KF, Kushida Y, Alford LM, Sale WS, Hennessey T, Gaertig J. Kinesin-13 regulates the quantity and quality of tubulin inside cilia. Molecular Biology of the Cell 2015;26(3):478-94.

Venkatasubramanian G. Understanding schizophrenia as a disorder of consciousness: biological correlates and translational implications from quantum theory perspectives. Clinical Psychopharmacology and Neuroscience 2015;13(1):36-47.

Volle J, Brocard J, Saoud M, Gory-Faure S, Brunelin J, Andrieux A, Suaud-Chagny MF. Reduced expression of STOP/MAP6 in mice leads to cognitive deficits. Schizophrenia Bulletin 2012;39(5):969-78.

Wang W, Cao L, Wang C, Gigant B, Knossow M. Kinesin, 30 years later: Recent insights from structural studies. Protein Science 2015;24(7):1047-56.

Weisenberg RC. Microtubule formation in vitro in solutions containing low calcium concentrations. Science 1972;177(4054):1104-5.

Weisenberg RC, Deery WJ, Dickinson PJ. Tubulin-nucleotide interactions during the polymerization and depolymerization of microtubules. Biochemistry 1976;15(19):4248-54.

Winterer G. Why do patients with schizophrenia smoke?. Current Opinion in Psychiatry 2010;23(2):112-9.

Woodruff JB, Wueseke O, Hyman AA. Pericentriolar material structure and dynamics. Philosophical Transactions of Royal Society B 2014;369(1650):20130459.

Wong GT, Chang RC, Law AC. A breach in the scaffold: the possible role of cytoskeleton dysfunction in the pathogenesis of major depression. Ageing Research Reviews 2013;12(1):67-75.

Wong ML, O'kirwan F, Hannestad JP, Irizarry KJ, Elashoff D, Licinio J. St John's wort and imipramine-induced gene expression profiles identify cellular functions relevant to antidepressant action and novel pharmacogenetic candidates for the phenotype of antidepressant treatment response. Molecular Psychiatry 2004;9(3):237-51.

Yuen EY, Yan Z. Cellular mechanisms for dopamine D4 receptor-induced homeostatic regulation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. Journal of Biological Chemistry 2011; 286(28): 24957-65.

Supporting Agencies

Antidepressants, Autism, Cytoskeleton, Microtubules, Schizophrenia, Tensegrity

| NeuroScience + QuantumPhysics> NeuroQuantology :: Copyright 2001-2017