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Convergent evidence for impaired AKT1-GSK3β signaling in schizophrenia

Nature Genetics volume 36, pages 131–137 (2004)Cite this article

Abstract

AKT-GSK3β signaling is a target of lithium and as such has been implicated in the pathogenesis of mood disorders. Here, we provide evidence that this signaling pathway also has a role in schizophrenia. Specifically, we present convergent evidence for a decrease in AKT1 protein levels and levels of phosphorylation of GSK3β at Ser9 in the peripheral lymphocytes and brains of individuals with schizophrenia; a significant association between schizophrenia and an AKT1 haplotype associated with lower AKT1 protein levels; and a greater sensitivity to the sensorimotor gating–disruptive effect of amphetamine, conferred by AKT1 deficiency. Our findings support the proposal that alterations in AKT1-GSK3β signaling contribute to schizophrenia pathogenesis and identify AKT1 as a potential schizophrenia susceptibility gene. Consistent with this proposal, we also show that haloperidol induces a stepwise increase in regulatory phosphorylation of AKT1 in the brains of treated mice that could compensate for an impaired function of this signaling pathway in schizophrenia.

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Figure 1: Lower AKT1 protein levels in the lymphocytes and frontal cortex of individuals with schizophrenia.
Figure 2: Reduced phosphorylation of GSK3β at Ser9 in the lymphocytes and frontal cortex of individuals with schizophrenia.
Figure 3: Preferential transmission to individuals with schizophrenia of an AKT1 haplotype associated with lower AKT1 protein levels.
Figure 4: AKT1 deficiency confers increased sensitivity to the sensorimotor gating–disruptive effect of amphetamine.
Figure 5: Haloperidol effects on phosphorylation of AKT1.

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References

  1. Coyle, J.T. & Duman, R.S. Finding the intracellular signaling pathways affected by mood disorder treatments. Neuron 38, 157–160 (2003).

    Article  CAS  Google Scholar 

  2. Greengard, P. Neurobiology of slow synaptic transmission. Science 294, 1024–1029 (2001).

    Article  CAS  Google Scholar 

  3. Winder, D.G. et al. ERK plays a regulatory role in induction of LTP by θ frequency stimulation and its modulation by β-adrenergic receptors. Neuron 24, 715–726 (1999).

    Article  CAS  Google Scholar 

  4. Lin, C.H. et al. A Role for the PI-3 kinase signaling pathway in fear conditioning and synaptic plasticity in the amygdala. Neuron 31, 841–851 (2001).

    Article  CAS  Google Scholar 

  5. Cho, H., Thorvaldsen, J.L., Chu, Q., Feng, F. & Birnbaum, M.J. Akt1/PKBα is required for normal growth but dispensable for maintenance of glucose homeostasis in mice. J. Biol. Chem. 276, 38349–38352 (2001).

    Article  CAS  Google Scholar 

  6. Braff, D.L., Geyer, M.A. & Swerdlow, N.R. Human studies of prepulse inhibition of startle: normal subjects, patient groups, and pharmacological studies. Psychopharmacology (Berl.) 156, 234–258 (2001).

    Article  CAS  Google Scholar 

  7. Torrey, F., Webster, M., Knable, M., Johnston, N. & Yolken, R.H. The Stanley Foundation brain collection and Neuropathology Consortium. Schiz. Res. 44, 151–155 (2000).

    Article  CAS  Google Scholar 

  8. Vanhaesebroeck, B. & Alessi, D.R. The PI3K-PDK1 connection: more than just a road to PKB. Biochem. J. 346, 561–576 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Detera-Wadleigh, S.D. et al. A high-density genome scan detects evidence for a bipolar-disorder susceptibility locus on 13q32 and other potential loci on 1q32 and 18p11.2. Proc. Natl. Acad. Sci. USA 96, 5604–5609 (1999).

    Article  CAS  Google Scholar 

  10. Segurado, R. et al. Genome scan meta-analysis of schizophrenia and bipolar disorder, part III: Bipolar disorder. Am. J. Hum. Genet. 73, 49–62 (2003).

    Article  CAS  Google Scholar 

  11. Toyota, T., Yamada, K., Detera-Wadleigh, S.D. & Yoshikawa, T. Analysis of a cluster of polymorphisms in AKT1 gene in bipolar pedigrees: a family-based association study. Neurosci. Lett. 339, 5–8 (2003).

    Article  CAS  Google Scholar 

  12. Swerdlow, N.R. & Geyer, M.A. Using an animal model of deficient sensorimotor gating to study the pathophysiology and new treatments of schizophrenia. Schizophr. Bull. 24, 285–301 (1998).

    Article  CAS  Google Scholar 

  13. Blume-Jensen, P. & Hunter, T. Oncogenic kinase signaling. Nature 411, 355–365 (2001).

    Article  CAS  Google Scholar 

  14. Chalecka-Franaszek, E. & Chuang, D.M. Lithium activates the serine/threonine kinase AKT-1 and suppresses glutamate-induced inhibition of AKT-1 activity in neurons. Proc. Natl. Acad. Sci. USA 96, 8745–8750 (1999).

    Article  CAS  Google Scholar 

  15. De Sarno, P., Li, X. & Jope, R.S. Regulation of AKT and glycogen synthase kinase-3 β phosphorylation by sodium valproate and lithium. Neuropharmacology 43, 1158–1164 (2002).

    Article  CAS  Google Scholar 

  16. Berrettini, W.H. Are schizophrenic and bipolar disorders related? A review of family and molecular studies. Biol. Psychiatry 48, 531–538 (2000).

    Article  CAS  Google Scholar 

  17. Scheid, M.P. & Woodgett, J.R. PKB/AKT: functional insights from genetic models. Nat. Rev. Mol. Cell Biol. 2, 760–768 (2001).

    Article  CAS  Google Scholar 

  18. Harwood, A.J. Regulation of GSK-3: a cellular multiprocessor. Cell 105, 821–824 (2001).

    Article  CAS  Google Scholar 

  19. Markus, A., Zhong, J. & Snider, W.D. Raf and AKT mediate distinct aspects of sensory axon growth. Neuron 35, 65–76 (2002).

    Article  CAS  Google Scholar 

  20. Beffert, U. et al. Reelin-mediated signaling locally regulates protein kinase B/AKT and glycogen synthase kinase 3β. J. Biol. Chem. 277, 49958–49964 (2002).

    Article  CAS  Google Scholar 

  21. Knable, M.B., Torrey, E.F., Webster, M.J. & Bartko, J.J. Multivariate analysis of prefrontal cortical data from the Stanley Foundation Neuropathology Consortium. Brain Res. Bull. 55, 651–659 (2001).

    Article  CAS  Google Scholar 

  22. Li, B.S. et al. Cyclin-dependent kinase-5 is involved in neuregulin-dependent activation of phosphatidylinositol 3-kinase and Akt activity mediating neuronal survival. J. Biol. Chem. 278, 35702–35709 (2003).

    Article  CAS  Google Scholar 

  23. Wang, Q. et al. Control of synaptic strength, a novel function of Akt. Neuron 38, 915–928 (2003).

    Article  CAS  Google Scholar 

  24. Akama, K.T. & McEwen, B.S. Estrogen stimulates postsynaptic density-95 rapid protein synthesis via the Akt/protein kinase B pathway. J. Neurosci. 23, 2333–2339 (2003).

    Article  CAS  Google Scholar 

  25. Mizuno, M. et al. Phosphatidylinositol 3-kinase: a molecule mediating BDNF-dependent spatial memory formation. Mol. Psychiatry 8, 217–224 (2003).

    Article  CAS  Google Scholar 

  26. Graef, I.A. et al. L-type calcium channels and GSK-3 regulate the activity of NF-ATc4 in hippocampal neurons. Nature 401, 703–708 (1999).

    Article  CAS  Google Scholar 

  27. Gerber, D.J. et al. Evidence for association of schizophrenia with genetic variation in the 8p21.3 gene, PPP3CC, encoding the calcineurin gamma subunit. Proc. Natl. Acad. Sci. USA 100, 8993–8998 (2003).

    Article  CAS  Google Scholar 

  28. Miyakawa, T. et al. Conditional calcineurin knockout mice exhibit multiple abnormal behaviors related to schizophrenia. Proc. Natl. Acad. Sci. USA 100, 8987–8992 (2003).

    Article  CAS  Google Scholar 

  29. Dudbridge, F. Pedigree disequilibrium tests for multilocus haplotypes. Genet. Epidemiol. 25, 115–121 (2003).

    Article  Google Scholar 

  30. Lewontin, R.C. On measures of gametic disequilibrium. Genetics 120, 849–852 (1988).

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank S. Demars, C. Frazier and S. Brenner for technical assistance and the MRC Brain Bank and the Stanley Foundation Brain Consortium for samples. Postmortem brains were donated by the Stanley Foundation Brain Consortium courtesy of L. B. Bigelow, J. Cervenak, M. M. Herman, T. M. Hyde, J. E. Kleinman, J. D. Paltàn, R. M. Post, E. F. Torrey, M. J. Webster and R. H. Yolken. The NIMH samples were collected in three projects that participated in the NIMH Schizophrenia Genetics Initiative. From 1991–1997, the Principal Investigators and Co-Investigators were as follows: (i) Harvard University, Boston, Massachusetts: M. T. Tsuang, S. Faraone and J. Pepple; (ii) Washington University, St. Louis, Missouri: C. R. Cloninger, T. Reich and D. Svrakic; and (iii) Columbia University, New York, New York: C. Kaufmann, D. Malaspina and J. H. Friedman. This work was funded in part by the Rockefeller Brothers Fund (M.K. and J.A.G.), New York City Council Speaker's Fund and the EJLB Foundation (J.A.G.).

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  1. The Rockefeller University, Laboratory of Human Neurogenetics, 1230 York Avenue, Box #313, New York, 10021, New York, USA

    Effat S Emamian, Diana Hall & Maria Karayiorgou

  2. Department of Physiology & Cellular Biophysics, Columbia University, College of Physicians & Surgeons, Center for Neurobiology & Behavior, 630 W. 168th Street, P&S 11–519, New York, 10032, New York, USA

    Effat S Emamian & Joseph A Gogos

  3. Howard Hughes Medical Institute, University of Pennsylvania School of Medicine, Philadelphia, 19104, Pennsylvania, USA

    Morris J Birnbaum

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Correspondence to Maria Karayiorgou or Joseph A Gogos.

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Emamian, E., Hall, D., Birnbaum, M. et al. Convergent evidence for impaired AKT1-GSK3β signaling in schizophrenia. Nat Genet 36, 131–137 (2004). https://doi.org/10.1038/ng1296

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