Altered immunoreactivity of complexin protein in prefrontal cortex in severe mental illness

Abstract

Recent imaging and postmortem studies suggest that impaired connectivity is involved in the pathophysiology of schizophrenia and major affective disorders. We investigated the presynaptic proteins complexin (Cx) I and Cx II in postmortem prefrontal cortex in schizophrenia (n = 13; six suicide, seven nonsuicide), major depression (n = 11, all suicide) and controls (n = 11) with an enzyme-linked immunoadsorbent assay (ELISA). Overall analysis indicated a significant difference between groups (F = 3.93, P = 0.007). Cx I (enriched in inhibitory terminals) was decreased 33% in schizophrenia (26% in schizophrenia/nonsuicide, 42% in schizophrenia/suicide) and 27% in major depression. Cx II (enriched in excitatory terminals) was not significantly different. Analysis of the ratio of Cx II/Cx I was carried out as an indication of the balance of excitatory to inhibitory terminals. A significant difference between groups (ANOVA, F = 6.42, P = 0.005) was observed. The mean value of Cx II/Cx I was significantly increased by 34% in schizophrenia (26% in schizophrenia/nonsuicide and 43% in schizophrenia/suicide) and by 32% in depression compared with control (Student-NewmanKeuls test, P = 0.05). Immunoreactivities of the two complexins were highly correlated in all groups. However, compared with controls and depression, samples from cases with schizophrenia appeared to have relatively less Cx I for similar amounts of Cx II. Immunocytochemical studies of rat frontal cortex after 3 weeks treatment with chlorpromazine, trifluoperazine or haloperidol revealed no differences in complexins, synaptophysin, SNAP-25, syntaxin or VAMP in comparison with animals treated with vehicle. Alterations of complexins may contribute to the molecular substrate for abnormalities of neural connectivity in severe mental disorders.

Presynaptic proteins in the prefrontal cortex of patients with schizophrenia and rats with abnormal prefrontal development

“…30,74 No change in various synapse-associated proteins was reported in the rat cortex after chronic treatment with perphenazine 75 and chlorpromazine, trifluoperazine and haloperidol. 76 We found a weak positive correlation of syntaxin levels with the last recorded dose of antipsychotics but no other synaptic protein was affected by any of the documented treatment variables. Hence, we have no evidence that medication was a major factor in our analysis but we cannot exclude such a possibility.…”

“…It is also possible that antipsychotic treatment may have confounded our results. However, in the rat studies VAMP protein and mRNA was not altered in PFC, 69,76 but significantly reduced in the nucleus accumbens. 69 Other confounding factors It is possible that the relatively low accuracy and precision of an immunoblotting method precluded detection of changes in the abundance of most proteins in this study.…”

Upregulation of CB1 receptors and agonist-stimulated [35S]GTPγS binding in the prefrontal cortex of depressed suicide victims

“…Disturbances in pre-and postsynaptic proteins in DS have been reported. 28 A number of Figure 2 The density of CB 1 receptor was estimated in prefrontal cortical membranes of DS (10) and matched controls (10). Data are mean7SEM of two to three experiments, each assayed in duplicate.…”

A Novel Mechanism and Treatment Target for Presynaptic Abnormalities in Specific Striatal Regions in Schizophrenia

“…Accessory factors also modulate SNARE complex formation, stability, and disassembly. Some interacting proteins are already known to be altered in schizophrenia, such as septin-5 and complexins (Pennington et al, 2008;Sawada et al, 2002). Future work is required to determine the possible roles for these factors in the increase in SNARE complexes.…”