Altered Complexin Expression in Psychiatric and Neurological Disorders: Cause or Consequence?

  • Brose, Nils (Department of Molecular Neurobiology, Max Planck Institute of Experimental Medicine)
  • Received : 2008.02.13
  • Accepted : 2008.02.15
  • Published : 2008.02.29


Complexins play a critical role in the control of fast synchronous neurotransmitter release. They operate by binding to trimeric SNARE complexes consisting of the vesicle protein Synaptobrevin and the plasma membrane proteins Syntaxin and SNAP-25, which are key executors of membrane fusion reactions. SNARE complex binding by Complexins is thought to stabilize and clamp the SNARE complex in a highly fusogenic state, thereby providing a pool of readily releasable synaptic vesicles that can be released quickly and synchronously in response to an action potential and the concomitant increase in intra-synaptic $Ca^{2+}$ levels. Genetic elimination of Complexins from mammalian neurons causes a strong reduction in evoked neurotransmitter release, and altered Complexin expression levels with consequent deficits in synaptic transmission were suggested to contribute to the etiology or pathogenesis of schizophrenia, Huntington's disease, depression, bipolar disorder, Parkinson's disease, Alzheimer's disease, traumatic brain injury, Wernicke's encephalopathy, and fetal alcohol syndrome. In the present review I provide a summary of available data on the role of altered Complexin expression in brain diseases. On aggregate, the available information indicates that altered Complexin expression levels are unlikely to have a causal role in the etiology of the disorders that they have been implicated in, but that they may contribute to the corresponding symptoms.


Bipolar Disorder;Complexin;Depression;Huntington's Disease;Neurodegenerative Diseases;Schizophrenia;SNARE Complex;Synaptic Transmission;Synaptic Vesicle Fusion


Supported by : Max Planck Society


  1. Barr, A.M., Hofmann, C.E., Phillips, A.G., Weinberg, J., and Honer, W.G. (2005). Prenatal ethanol exposure in rats decreases levels of complexin proteins in the frontal cortex. Alcohol Clin. Exp. Res. 29, 1915-1920
  2. Beasley, C.L., Pennington, K., Behan, A., Wait, R., Dunn, M.J., and Cotter, D. (2006). Proteomic analysis of the anterior cingulate cortex in the major psychiatric disorders: evidence for disease-associated changes. Proteomics 6, 3414-3425
  3. Butterfield, D.A. and Boyd-Kimball, D. (2004). Proteomics analysis in Alzheimer's disease: new insights into mechanisms of neurodegeneration. Int. Rev. Neurobiol. 61, 159-188
  4. Cha, J.H. (2007). Transcriptional signatures in Huntington's disease. Prog. Neurobiol. 83, 228-248
  5. Dubois, M., Vacher, P., Roger, B., Huyghe, D., Vandewalle, B., Kerr-Conte, J., Pattou, F., Moustaid-Moussa, N., and Lang, J. (2007). Glucotoxicity inhibits late steps of insulin exocytosis. Endocrinology 148, 1605-1614
  6. Glynn, D., Bortnick, R.A., and Morton, A.J. (2003). Complexin II is essential for normal neurological function in mice. Hum. Mol. Genet. 12, 2431-2448
  7. Ishizuka, T., Saisu, H., Odani, S., Kumanishi, T., and Abe, T. (1999). Distinct regional distribution in the brain of messenger RNAs for the two isoforms of synaphin associated with the docking/fusion complex. Neuroscience 88, 295-306
  8. Novikova, S.I., He, F., Cutrufello, N.J., and Lidow, M.S. (2006). Identification of protein biomarkers for schizophrenia and bipolar disorder in the postmortem prefrontal cortex using SELDI-TOF-MS ProteinChip profiling combined with MALDI-TOF- PSD-MS analysis. Neurobiol. Dis. 23, 61-76
  9. Pennington, K., Beasley, C.L., Dicker, P., Fagan, A., English, J., Pariante, C.M., Wait, R., Dunn, M.J., and Cotter, D.R. (2007). Prominent synaptic and metabolic abnormalities revealed by proteomic analysis of the dorsolateral prefrontal cortex in schizophrenia and bipolar disorder. Mol. Psychiatry [Epub ahead of print]
  10. Raedler, T.J. and Wiedemann, K. (2006). CSF-studies in neuropsychiatric disorders. Neuro Endocrinol. Lett. 27, 297-305
  11. Reim, K., Mansour, M., Varoqueaux, F., McMahon, H.T., Sudhof, T.C., Brose, N., and Rosenmund, C. (2001). Complexins regulate a late step in $Ca^{2+}$-dependent neurotransmitter release. Cell 104, 71-81
  12. Rosenmund, C., Rettig, J., and Brose, N. (2003). Molecular mechanisms of active zone function. Curr. Op. Neurobiol. 13, 509-519
  13. Schmidt, O., Schulenborg, T., Meyer, H.E., Marcus, K., and Hamacher, M. (2005). How proteomics reveals potential biomarkers in brain diseases. Exp. Rev. Proteomics 2, 901-913
  14. Sequeira, A. and Turecki, G. (2006). Genome wide gene expression studies in mood disorders. OMICS 10, 444-454
  15. Tang, J., Maximov, A., Shin, O.H., Dai, H., Rizo, J., and Sudhof, T.C. (2006). A complexin/synaptotagmin 1 switch controls fast synaptic vesicle exocytosis. Cell 126, 1175-1187
  16. Wojcik, S.M. and Brose, N. (2007). Regulation of membrane fusion in synaptic excitation-secretion coupling: speed and accuracy matter. Neuron 55, 11-24
  17. Zabel, C. and Klose, J. (2004). Influence of Huntington's disease on the human and mouse proteome. Int. Rev. Neurobiol. 61, 241-283
  18. Freeman, W. and Morton, A.J. (2004a). Differential messenger RNA expression of complexins in mouse brain. Brain Res. Bull. 63, 33-44
  19. Glynn, D., Drew, C.J., Reim, K., Brose, N., and Morton, A.J. (2005). Profound ataxia in complexin I knockout mice masks a complex phenotype that includes exploratory and habituation deficits. Hum. Mol. Genet. 14, 2369-2385
  20. Knable, M.B., Barci, B.M., Webster, M.J., Meador-Woodruff, J., and Torrey, E.F. (2004). Molecular abnormalities of the hippocampus in severe psychiatric illness: postmortem findings from the stanley neuropathology consortium. Mol. Psychiatry 9, 609-620, 544
  21. Schaub, J.R., Lu, X., Doneske, B., Shin, Y.K., and McNew, J.A. (2006). Hemifusion arrest by complexin is relieved by $Ca^{2+}$- synaptotagmin I. Nat. Struct. Mol. Biol. 13, 748-750
  22. Basso, M., Giraudo, S., Corpillo, D., Bergamasco, B., Lopiano, L., and Fasano, M. (2004). Proteome analysis of human substantia nigra in Parkinson's disease. Proteomics 4, 3943-3952
  23. Sawada, K., Barr, A.M., Nakamura, M., Arima, K., Young, C.E., Dwork, A.J., Falkai, P., Phillips, A.G., and Honer, W.G. (2005). Hippocampal complexin proteins and cognitive dysfunction in schizophrenia. Arch. Gen. Psychiatry 62, 263-272
  24. Witzmann, F.A., Li, J., Strother, W.N., McBride, W.J., Hunter, L., Crabb, D.W., Lumeng, L., and Li, T.K. (2003). Innate differences in protein expression in the nucleus accumbens and hippocampus of inbred alcohol-preferring and -nonpreferring rats. Proteomics 3, 1335-1344
  25. Hazell, A.S. and Wang, C. (2005). Downregulation of complexin I and complexin II in the medial thalamus is blocked by N-acetylcysteine in experimental Wernicke's encephalopathy. J. Neurosci. Res. 79, 200-207
  26. Jahn, R. and Scheller, R.H. (2006). SNAREs--engines for membrane fusion. Nat. Rev. Mol. Cell. Biol. 7, 631-643
  27. Nakahara, T., Motomura, K., Hashimoto, K., Ueki, H., Gotoh, L., Hondo, H., Tsutsumi, T., Kuroki, T., Hirano, M., and Uchimura, H. (2000). Long-term treatment with haloperidol decreases the mRNA levels of complexin I, but not complexin II, in rat prefrontal cortex, nucleus accumbens and ventral tegmental area. Neurosci. Lett. 290, 29-32
  28. Eastwood, S.L. and Harrison, P.J. (2001). Synaptic pathology in the anterior cingulate cortex in schizophrenia and mood disorders. A review and a Western blot study of synaptophysin, GAP-43 and the complexins. Brain Res. Bull. 55, 569-578
  29. Mirnics, K., Middleton, F.A., Marquez, A., Lewis, D.A., and Levitt, P. (2000). Molecular characterization of schizophrenia viewed by microarray analysis of gene expression in prefrontal cortex. Neuron 28, 53-67
  30. Morton, A.J., Faull, R.L., and Edwardson, J.M. (2001). Abnormalities in the synaptic vesicle fusion machinery in Huntington's disease. Brain Res. Bull. 56, 111-117
  31. Zink, M., Vollmayr, B., Gebicke-Haerter, P.J., Henn, F.A., and Thome, J. (2007). Reduced expression of complexins I and II in rats bred for learned helplessness. Brain Res. 1144, 202-208
  32. Eastwood, S.L. and Harrison, P.J. (2000). Hippocampal synaptic pathology in schizophrenia, bipolar disorder and major depression: a study of complexin mRNAs. Mol. Psychiatry 5, 425-432
  33. Takahashi, S., Yamamoto, H., Matsuda, Z., Ogawa, M., Yagyu, K., Taniguchi, T., Miyata, T., Kaba, H., Higuchi, T., Okutani, F., et al. (1995). Identification of two highly homologous presynaptic proteins distinctly localized at the dendritic and somatic synapses. FEBS Lett. 368, 455-460
  34. Glynn, D., Reim, K., Brose, N., and Morton, A.J. (2007a). Depletion of Complexin II does not affect disease progression in a mouse model of Huntington's disease (HD); support for role for complexin II in behavioural pathology in a mouse model of HD. Brain Res. Bull. 72, 108-120
  35. Jockusch, W.J., Speidel, D., Sigler, A., Sorensen, J.B., Varoqueaux, F., Rhee, J.S., and Brose, N. (2007). CAPS-1 and CAPS-2 are essential synaptic vesicle priming proteins. Cell 131, 796-808
  36. Lewis, D.A. and Mirnics, K. (2006). Transcriptome alterations in schizophrenia: disturbing the functional architecture of the dorsolateral prefrontal cortex. Prog. Brain Res. 158, 141-152
  37. Glynn, D., Sizemore, R.J., and Morton, A.J. (2007b). Early motor development is abnormal in complexin 1 knockout mice. Neurobiol. Dis. 25, 483-495
  38. Kishi, T., Ikeda, M., Suzuki, T., Kitajima, T., Yamanouchi, Y., Kinoshita, Y., Ozaki, N., and Iwata, N. (2006). No association of complexin1 and complexin2 genes with schizophrenia in a Japanese population. Schizophr. Res. 82, 185-189
  39. Giraudo, C.G., Eng, W.S., Melia, T.J., and Rothman, J.E. (2006). A clamping mechanism involved in SNARE-dependent exocytosis. Science 313, 676-680
  40. Rizo, J., Chen, X., and Arac, D. (2006). Unraveling the mechanisms of synaptotagmin and SNARE function in neurotransmitter release. Trends Cell Biol. 16, 339-350
  41. Yi, J.H., Hoover, R., McIntosh, T.K., and Hazell, A.S. (2006). Early, transient increase in complexin I and complexin II in the cerebral cortex following traumatic brain injury is attenuated by N-acetylcysteine. J. Neurotrauma 23, 86-96
  42. Zabel, C., Sagi, D., Kaindl, A.M., Steireif, N., Klare, Y., Mao, L., Peters, H., Wacker, M.A., Kleene, R., and Klose, J. (2006). Comparative proteomics in neurodegenerative and nonneurodegenerative diseases suggest nodal point proteins in regulatory networking. J. Proteome Res. 5, 1948-1958
  43. Drew, C.J., Kyd, R.J., and Morton, A.J. (2007). Complexin 1 knockout mice exhibit marked deficits in social behaviours but appear to be cognitively normal. Hum. Mol. Genet. 16, 2288-2305
  44. Tannenberg, R.K., Scott, H.L., Tannenberg, A.E., and Dodd, P.R. (2006). Selective loss of synaptic proteins in Alzheimer's disease: evidence for an increased severity with APOE varepsilon4. Neurochem. Int. 49, 631-639
  45. Xue, M., Reim, K., Chen, X., Chao, H.T., Deng, H., Rizo, J., Brose, N., and Rosenmund, C. (2007). Distinct domains of complexin I differentially regulate neurotransmitter release. Nat. Struct. Mol. Biol. 14, 949-958
  46. Yamada, M., Saisu, H., Ishizuka, T., Takahashi, H., and Abe, T. (1999). Immunohistochemical distribution of the two isoforms of synaphin/complexin involved in neurotransmitter release: localization at the distinct central nervous system regions and synaptic types. Neuroscience 93, 7-18
  47. Eastwood, S.L., Burnet, P.W., and Harrison, P.J. (2000). Expression of complexin I and II mRNAs and their regulation by antipsychotic drugs in the rat forebrain. Synapse 36, 167-177<167::AID-SYN2>3.0.CO;2-D
  48. Eastwood, S.L., Cotter, D., and Harrison, P.J. (2001). Cerebellar synaptic protein expression in schizophrenia. Neuroscience 105, 219-229
  49. Huntwork, S. and Littleton, J.T. (2007). A complexin fusion clamp regulates spontaneous neurotransmitter release and synaptic growth. Nat. Neurosci. 10, 1235-1237
  50. Edwardson, J.M., Wang, C.T., Gong, B., Wyttenbach, A., Bai, J., Jackson, M.B., Chapman, E.R., and Morton, A.J. (2003). Expression of mutant huntingtin blocks exocytosis in PC12 cells by depletion of complexin II. J. Biol. Chem. 278, 30849-30853
  51. Augustin, I., Rosenmund, C., Sudhof, T.C., and Brose, N. (1999). Munc13-1 is essential for fusion competence of glutamatergic synaptic vesicles. Nature 400, 457-461
  52. Salimi, K., Glantz, L.A., Hamer, R.M., German, T.T., Gilmore, J.H., and Jarskog, L.F. (2008). Regulation of Complexin 1 and Complexin 2 in the developing human prefrontal cortex. Synapse 62, 273-282
  53. Melia, T.J., Jr. (2007). Putting the clamps on membrane fusion: how complexin sets the stage for calcium-mediated exocytosis. FEBS Lett. 581, 2131-2139
  54. Morton, A.J. and Edwardson, J.M. (2001). Progressive depletion of complexin II in a transgenic mouse model of Huntington's disease. J. Neurochem. 76, 166-172
  55. Reim, K., Wegmeyer, H., Brandstatter, J.H., Xue, M., Rosenmund, C., Dresbach, T., Hofmann, K., and Brose, N. (2005). Structurally and functionally unique complexins at retinal ribbon synapses. J. Cell Biol. 169, 669-680
  56. McMahon, H.T., Missler, M., Li, C., and Sudhof, T.C. (1995). Complexins: cytosolic proteins that regulate SNAP receptor function. Cell 83, 111-119
  57. Lee, H.J., Song, J.Y., Kim, J.W., Jin, S.Y., Hong, M.S., Park, J.K., Chung, J.H., Shibata, H., and Fukumaki, Y. (2005). Association study of polymorphisms in synaptic vesicleassociated genes, SYN2 and CPLX2, with schizophrenia. Behav. Brain Funct. 1, 15
  58. Varoqueaux, F., Aramuni, G., Rawson, R.L., Mohrmann, R., Missler, M., Gottmann, K., Zhang, W., Sudhof, T.C., and Brose, N. (2006). Neuroligins determine synapse maturation and function. Neuron 51, 741-754
  59. Eastwood, S.L. and Harrison, P.J. (2005). Decreased expression of vesicular glutamate transporter 1 and complexin II mRNAs in schizophrenia: further evidence for a synaptic pathology affecting glutamate neurons. Schizophr. Res. 73, 159-172
  60. Patel, S., Sinha, A., and Singh, M.P. (2007). Identification of differentially expressed proteins in striatum of maneb-and paraquat-induced Parkinson's disease phenotype in mouse. Neurotoxicol. Teratol. 29, 578-585
  61. Freeman, W. and Morton, A.J. (2004b). Regional and progressive changes in brain expression of complexin II in a mouse transgenic for the Huntington's disease mutation. Brain Res. Bull. 63, 45-55
  62. Harrison, P.J. and Eastwood, S.L. (1998). Preferential involvement of excitatory neurons in medial temporal lobe in schizophrenia. Lancet 352, 1669-1673
  63. Mufson, E.J., Counts, S.E., Che, S., and Ginsberg, S.D. (2006). Neuronal gene expression profiling: uncovering the molecular biology of neurodegenerative disease. Prog. Brain Res. 158, 197-222
  64. Zink, M., Rapp, S., Gebicke-Haerter, P.J., Henn, F.A., and Thome, J. (2005). Antidepressants differentially affect expression of complexin I and II RNA in rat hippocampus. Psychopharmacology 181, 560-565
  65. Yamauchi, Y., Qin, L.H., Nishihara, M., Sawada, K., Kato, K., and Inoue, S. (2005). Vulnerability of synaptic plasticity in the complexin II knockout mouse to maternal deprivation stress. Brain Res. 1056, 59-67
  66. DiProspero, N.A., Chen, E.Y., Charles, V., Plomann, M., Kordower, J.H., and Tagle, D.A. (2004). Early changes in Huntington's disease patient brains involve alterations in cytoskeletal and synaptic elements. J. Neurocytol. 33, 517-533
  67. Drabik, A., Bierczynska-Krzysik, A., Bodzon-Kulakowska, A., Suder, P., Kotlinska, J., and Silberring, J. (2007). Proteomics in neurosciences. Mass Spectrom. Rev. 26, 432-450
  68. Sawada, K., Young, C.E., Barr, A.M., Longworth, K., Takahashi, S., Arango, V., Mann, J.J., Dwork, A.J., Falkai, P., Phillips, A.G., et al. (2002). Altered immunoreactivity of complexin protein in prefrontal cortex in severe mental illness. Mol. Psychiatry 7, 484-492