Hippocampal complexin proteins and cognitive dysfunction in schizophrenia.
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.


OBJECTIVE
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.


METHODS
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.


METHODS
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.
Sawada
Ken
K
Department of Neuropsychiatry, Kochi Medical School, Kochi, Japan.
Barr
Alasdair M
AM
Nakamura
Masato
M
Arima
Kunimasa
K
Young
Clint E
CE
Dwork
Andrew J
AJ
Falkai
Peter
P
Phillips
Anthony G
AG
Honer
William G
WG
D033942:Adaptor Proteins, Vesicular Transport; D000368:Aged; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects; D003072:Cognition Disorders / Q000139:chemically induced / Q000175:diagnosis* / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D006220:Haloperidol / Q000494:pharmacology; D006624:Hippocampus / Q000378:metabolism* / Q000503:physiopathology; D006801:Humans; D007150:Immunohistochemistry; D007649:Ketamine / Q000494:pharmacology; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D026901:Membrane Transport Proteins / Q000378:metabolism; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000378:metabolism* / Q000502:physiology; D017729:Presynaptic Terminals / Q000378:metabolism / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012559:Schizophrenia / Q000175:diagnosis* / Q000378:metabolism / Q000503:physiopathology; D012565:Schizophrenic Psychology; D050598:Vesicular Glutamate Transport Protein 1; D050495:Vesicular Inhibitory Amino Acid Transport Proteins
D033942:Adaptor Proteins, Vesicular Transport; D014150:Antipsychotic Agents; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; C493464:SLC17A7 protein, human; C493466:Slc17a7 protein, rat; D050598:Vesicular Glutamate Transport Protein 1; D050495:Vesicular Inhibitory Amino Acid Transport Proteins; C095992:complexin I; C095993:complexin II; C493406:vesicular GABA transporter; D007649:Ketamine; D006220:Haloperidol