Abstract
Schizophrenia is a common and severe psychiatric disorder of unknown etiology. Numerous neuropathological studies have found subtle structural changes in limbic structures, especially medial temporal lobe structures and the gyrus cinguli. To test the hypothesis that synaptic disturbances are involved in the pathogenesis of schizophrenia, we studied the growth-associated protein 43 (GAP-43), a protein localized to presynaptic terminals, suggested to be involved in establishment and remodeling of synaptic connections, in postmortem brain tissue, using quantitative Western blotting immunohistochemistry. The material consisted of brain tissue from 17 schizophrenics (80±11 yr), diagnosed according to the DSM-III-R criteria, and 20 age-matched controls (75±13 yr). Quantitative analyses showed increased GAP-43 protein levels in schizophrenic compared to control brains, both in the hippocampus (2.43±0.78 vs 1.00±0.29; p<0.0001) and in the gyrus cinguli (1.52±0.21 vs 1.00±0.35; p<0.0001). Also by immuno-histochemistry, increased GAP-43 staining was found in schizophrenic compared with control brains, throughout all layers of the gyrus cinguli and the hippocampus. Anomalous synaptic sprouting and reorganization, with resultant “miswiring,” as well as a defect in synaptic pruning have been hypothesized to be pathogenetic factors in schizophrenia. We suggest that a decreased synaptic density, whether caused by disturbed development or damage/degeneration, may elicit a reactive synaptogenesis (reflected by an increase in GAP-43), which may be functional or anomalous. Synaptic pathology in the limbic system may be of importance in the development of psychotic symptoms in schizophrenia.
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Adolfsson R., Gottfries C. G., Nyström L., and Winblad B. (1981) Prevalence of dementia disorders in institutionalized Swedish old people, The work load imposed by caring for these patients. Acta. Psychiat. Scand. 62, 225–244.
American Psychiatric Association (1987) Diagnostic and Statistical Manual of Mental Disorders, 3rd ed., rev. American Psychiatric Association, Washington, DC.
Arnold S. E., Lee V. M. Y., Gur R. E., and Trojanowski J. Q. (1991) Abnormal expression of two micro-tubule-associated proteins (MAP2 and MAP5) in specific subfields of the hippocampal formation in schizophrenia. Proc. Natl. Acad. Sci. USA 88, 10,850–10,854.
Arnold S. E., Franz B. R., Gur R. C., Gur R. E., Shapiro R. M., Moberg P. J., et al. (1995) Smaller neuron size in schizophrenia in hippocampal subfields that mediate cortical-hippocampal interactions. Am. J. Psych. 152, 738–748.
Basi G. S. (1987) Primary structure and transcriptional regulation of GAP-43, a protein associated with nerve growth. Cell 49, 785–791.
Benes F. M. (1993) Neurobiological investigations in cingulate cortex of schizophrenic brain. Schizophr. Bull. 19, 537–549.
Benes F. M., Davidson J., and Bird E. D. (1986) Quantitative cytoarchitectural studies of the cerebral cortex of schizophrenics. Arch. Gen. Psychiatry 43, 31–35.
Benes F. M., Sorensen I., and Bird E. D. (1991a) Reduced neuronal size in posterior hippocampus of schizophrenic patients. Schizophr. Bull. 17, 597–608.
Benes F. M., McSparren J., Bird E. D., SanGiovanni J. P., and Vincent S. L. (1991b) Deficits in small interneurons in prefrontal and cingulate cortices of schizophrenic and schizoaffective patients. Arch. Gen. Psych. 48, 996–1001.
Benowitz L. I. and Routtenberg A. (1997) GAP-43: an intrinsic determinant of neuronal development and plasticity. Trends Neurosci. 20, 84–91.
Benowitz L. I., Shashoua V. E., and Yoon M. (1981) Specific changes in rapidly transported proteins during regeneration of goldfish optic nerve. J. Neurosci. 1, 300–307.
Benowitz L. I., Perrone-Bizzozero N. I., Finklestein S. P., and Bird E. D. (1989) Localization of the growth-associated phosphoprotein GAP-43 (B-50, F1) in the human cerebral cortex. J. Neurosci. 9, 990–995.
Benowitz L. I., Rodriguez W. R., and Neve R. L. (1990) The pattern of GAP-43 immunostaining changes in the rat hippocampal formation during reactive synaptogenesis. Brain Res. Mol. Brain Res. 8, 17–23.
Blennow K., Bogdanovic N., Alafuzoff I., Ekman R., and Davidsson P. (1996a) Synaptic pathology in Alzheimer’s disease: relation to severity of dementia, but not to senile plaques, neurofibrillary tangles, or the ApoE4 allele. J. Neural. Transm. (P-D section) 103, 603–618.
Blennow K., Davidsson P., Gottfries C. G., Ekman R., and Heilig M. (1996b) Synaptic degeneration in thalamus in schizophrenia. Lancet 348, 692,693.
Bogdanovic N., Davidsson P., Gottfries J., Volkman I., Winblad B., and Blennow K. (1999) Regional and cellular distribution of synaptic proteins in the normal human brain. Submitted.
Bogerts B. (1993). Recent advance in the neuropathology of schizophrenia. Schizophr. Bull. 19, 431–445.
Davidsson P., Jahn R., Bergquist J., Ekman R., and Blennow K. (1996) Synaptotagmin, a synaptic vesicle protein, is present in human cerebrospinal fluid: a new biochemical marker for synaptic pathology in Alzheimer’s disease? Mol. Chem. Neuropathol. 27, 195–210.
De la Monte S. M., Federoff H. J., Ng S. C., Grabczyk E., and Fishman M. C. (1989) GAP-43 gene expression during development: persistence in a distinct set of neurons in the mature central nervous system. Dev. Brain Res. 46, 161–168.
Dolan R. J., Fletcher P., Frith C. D., Friston K. J., Frackowiak R. S., and Grasby P. M. (1995) Dopaminergic modulation of impaired cognitive activation in the anterior cingulate cortex in schizophrenia. Nature 378, 180–182.
Eastwood S. L. and Harrison P. J. (1995) Decreased synaptophysin in the medial temporal lobe in schizophrenia demonstrated using immunoautoradiography. Neuroscience 69, 339–343.
Falkai P. and Bogerts B. (1986) Cell loss in the hippocampus of schizophrenics. Eur. Arch. Psychiatr. Neurol. Sci. 236, 154–161.
Glantz L. A. and Lewis D. A. (1997) Reduction of synaptophysin immunoreactivity in the prefrontal cortex of subjects with schizophrenia. Arch. Gen. Psych. 54, 660–669.
Goldsmith S. K. and Joyce J. N. (1995) Alterations in hippocampal mossy fiber pathway in schizophrenia and Alzheimer’s disease. Biol. Psych. 37, 122–126.
Granger B. (1996) Synaptogenesis and synaptic pruning: role in triggering schizophrenia. Presse Med. 25, 1595–1598.
Gur R. E. and Pearlson G. D. (1993) Neuroimaging in schizophrenia research. Schizophr. Bull. 19, 337–353.
Harrison P. J., Eastwood S. L., Esiri M. M., and Zaidel D. W. (1996) Cytoarchitectural hippocampal asymmetries in schizophrenia. Schizophr. Res. 18, 180.
Horn D. and Ruppin E. (1995) Compensatory mechanisms in an attractor neural network model of schizophrenia. Neural. Computation 7, 182–205.
Jeste D. V. and Lohr J. B. (1989) Hippocampal pathologic findings in schizophrenia: a morphometric study. Arch. Gen. Psychiatry 46, 1019–1024.
Lin L. H., Boch S., Carpenter K., Rose M., and Norden J. J. (1992) Synthesis and transport of GAP-43 in entorhinal cortex neurons and perforant pathway during lesion-induced sprouting and reactive synaptogenesis. Brain Res. Mol. Brain Res. 14, 147–153.
Lowry O. H., Rosebrough N. J., Farr A. L., and Randall R. J. (1951) Protein measurement with the folin phenol reagent. J. Biol. Chem. 193, 265–275.
Meiri K. F., Pfenninger K. H., and Willard M. B. (1986) Growth-associated protein, GAP-43, a polypeptide that is induced when neurons extend, is a component of growth cones and correspond to pp46, a major polypeptide of a subcellular fraction enriched in growth cones. Proc. Natl. Acad. Sci. USA 83, 3537–3541.
Mercken M., Lübke U., Vandermeeren M., Gheuens J., and Oestreicher A. B. (1992) Immunocytochemical detection of the growth-associated protein B-50 by newly characterized monoclonal antibodies in human brain and muscle. J. Neurobiol. 23, 309–321.
Moore R. Y. and Bernstein M. E. (1989) Synaptogenesis in the rat suprachiasmatic nucleus demonstrated by electron microscopy and synapsin I immunoreactivity. J. Neurosci. 9, 2151–2162.
Neve R. L. and Bear M. F. (1989) Visual experience regulates gene expression in the developing striate cortex. Proc. Natl. Acad. Sci. USA 86, 4781–4784.
Noga J. T., Aylward E., Barta P. E., and Pearlson G. D. (1995) Cingulate gyrus in schizophrenic patients and normal volunteers. Psych. Res. 61, 201–208.
Olney J. W. and Farber N. B. (1995) Glutamate receptor dysfunction and schizophrenia. Arch. Gen. Psych. 52, 998–1007.
Pakkenberg B. (1987) Post-mortem study of chronic schizophrenic brains. Br. J. Psych. 151, 744–752.
Perrone-Bizzozero N. I., Sower A. C., Bird E. D., Benowitz L. I., Ivins K. J., and Neve R. L. (1996) Levels of the growth-associated protein GAP-43 are selectively increased in association cortices in schizophrenia. Proc. Natl. Acad. Sci. USA 93, 14,182–14,187.
Selemon L. D., Rajkowska G., and Goldman-Rakic P. S. (1995) Abnormally high neuronal density in the schizophrenic cortex: a morphometric analysis of prefrontal area 9 and occipital area 17. Arch. Gen. Psych. 52, 805–818.
Skene J. H. P. and Willard M. (1981) Changes in axonally transported proteins during axon regeneration and toad retinal ganglion cells. J. Cell. Biol. 89, 86–95.
Sower A. C., Bird E. D., and Perrone-Bizzozero N. I. (1995) Increased levels of GAP-43 protein in schizophrenic brain tissues demonstrated by a novel immuno-detection method. Mol. Chem. Neuropathol. 24, 1–11.
Stevens J. R. (1992) Abnormal reinnervation as a basis for schizophrenia: a hypothesis. Arch. Gen. Psych. 49, 238–243.
Terry R. D., Masliah E., Salmon D. P., Butters N., DeTeresa R., Hill R., et al. (1991) Physical basis of cognitive alterations in Alzheimer’s disease: synapse loss is the major correlate of cognitive impairment. Ann. Neurol. 30, 572–580.
Weinberger D. R. (1995) From neuropathology to neurodevelopment. Lancet 346, 552–557.
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Blennow, K., Bogdanovic, N., Gottfries, CG. et al. The growth-associated protein GAP-43 is increased in the hippocampus and in the gyrus cinguli in schizophrenia. J Mol Neurosci 13, 101–109 (1999). https://doi.org/10.1385/JMN:13:1-2:101
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DOI: https://doi.org/10.1385/JMN:13:1-2:101