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Hippocampal complexin proteins and cognitive dysfunction in schizophrenia.

AbstractBACKGROUND:
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 gamma-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 gamma-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.
AuthorsKen Sawada, Alasdair M Barr, Masato Nakamura, Kunimasa Arima, Clint E Young, Andrew J Dwork, Peter Falkai, Anthony G Phillips, William G Honer
JournalArchives of general psychiatry (Arch Gen Psychiatry) Vol. 62 Issue 3 Pg. 263-72 (Mar 2005) ISSN: 0003-990X [Print] United States
PMID15753239 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Adaptor Proteins, Vesicular Transport
  • Antipsychotic Agents
  • Membrane Transport Proteins
  • Nerve Tissue Proteins
  • SLC17A7 protein, human
  • Slc17a7 protein, rat
  • Vesicular Glutamate Transport Protein 1
  • Vesicular Inhibitory Amino Acid Transport Proteins
  • complexin I
  • complexin II
  • vesicular GABA transporter
  • Ketamine
  • Haloperidol
Topics
  • Adaptor Proteins, Vesicular Transport
  • Aged
  • Animals
  • Antipsychotic Agents (pharmacology)
  • Behavior, Animal (drug effects)
  • Cognition Disorders (chemically induced, diagnosis, metabolism)
  • Disease Models, Animal
  • Female
  • Haloperidol (pharmacology)
  • Hippocampus (metabolism, physiopathology)
  • Humans
  • Immunohistochemistry
  • Ketamine (pharmacology)
  • Male
  • Maze Learning (drug effects)
  • Membrane Transport Proteins (metabolism)
  • Middle Aged
  • Nerve Tissue Proteins (metabolism, physiology)
  • Presynaptic Terminals (metabolism, physiology)
  • Rats
  • Rats, Sprague-Dawley
  • Schizophrenia (diagnosis, metabolism, physiopathology)
  • Schizophrenic Psychology
  • Vesicular Glutamate Transport Protein 1
  • Vesicular Inhibitory Amino Acid Transport Proteins

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