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Ken Sawada, MD; Alasdair M. Barr, PhD; Masato Nakamura, MD; Kunimasa Arima, MD; Clint E. Young, PhD; Andrew J. Dwork, MD; Peter Falkai, MD; Anthony G. Phillips, PhD; William G. Honer, MD, FRCPC

Arch Gen Psychiatry. 2005;62:263-272.

Background  Converging neuroimaging and postmortem evidence indicates synaptic terminals are abnormal in schizophrenia. A putative molecular mechanism implicates abnormalities of proteins involved in the presynaptic secretory machinery, including the modulator proteins complexin I and complexin II.

Objectives  To determine the amount and distribution of complexin proteins in the hippocampus of subjects with schizophrenia, in parallel with markers for excitatory and inhibitory nerve terminals. The functional implications were also investigated.

Design  We used immunocytochemistry to study complexin I and complexin II proteins in hippocampus, as well as the vesicular transporters for -aminobutyric acid (GABA) and for glutamate. Immunocytochemical findings were correlated with cognitive function assessed through medical record review. To further explore the implications of the human findings, we studied rats exposed to haloperidol, amphetamine, and ketamine as well as rats trained in memory tasks.

Subjects  We studied hippocampal sections from 12 subjects with schizophrenia and 12 subjects with no known neuropsychiatric disorder.

Results  The absolute values and ratio of the hippocampal presynaptic proteins complexin II—complexin I were lower in subjects with schizophrenia. Disturbances in the complexin proteins in subjects with schizophrenia were greater than those observed for vesicular -aminobutyric acid or vesicular glutamate transporters. The lower complexin II–complexin I ratio in several hippocampal subfields in subjects with schizophrenia was inversely correlated with the severity of antemortem cognitive impairment. In contrast, the hippocampal complexin II–complexin I ratio was higher in rats trained in a memory task compared with untrained rats. Treatment of rats with antipsychotic drugs or with the psychotomimetic drugs amphetamine or ketamine did not alter the complexin II–complexin I ratio.

Conclusions  The pathology of hippocampal complexin proteins might play an important role in schizophrenia, especially concerning cognitive disturbances.

Author Affiliations: Department of Neuropsychiatry, Kochi Medical School, Kochi, Japan (Dr Sawada); Department of Psychiatry, University of British Columbia, Vancouver (Drs Barr, Young, Phillips, and Honer); Department of Psychiatry, National Center Hospital for Mental, Nervous, and Muscular Disorders, Tokyo, Japan (Drs Nakamura and Arima); Department of Neuroscience, New York State Psychiatric Institute, and Departments of Pathology and Psychiatry, Columbia University, New York (Dr Dwork); Department of Psychiatry, Saarland University, Homburg, Germany (Dr Falkai).

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