Upregulation of NRG-1 and VAMP-1 in human brain aggregates exposed to clozapine

Abstract

Growing genetic evidence has implicated a role for neuregulin-1 (NRG-1) in schizophrenia pathogenesis as well as alterations in SNAP receptor (SNARE) proteins at both gene and protein levels in post-mortem investigations. In relation to a potential therapeutic mechanism for atypical antipsychotic medications, clozapine has been shown to increase both NRG-1 levels and synaptic markers in rodents. As evidence continues to mount for a potential restoration in connectivity by antipsychotic medications being a mode of efficacy we chose to examine the effects of the atypical antipsychotic clozapine and the typical antipsychotic haloperidol on NRG-1 and SNARE protein transcripts in a human brain aggregates exposed to plasma levels chronically for a period of three weeks. At the end of this exposure period we performed quantitative real-time PCR to investigate the mRNA levels of NRG-1, VAMP-1 and SNAP-25. Overall we found that clozapine had the ability to upregulate NRG-1 (+3.58 fold change) and VAMP-1 (+1.92) while SNAP-25 remained unchanged. Changes for haloperidol exposed aggregates were below our cut-off of +1.5. Overall the results of our investigation lend further support to atypical antipsychotic medications having the potential to increase levels of neurotrophic and synaptic markers such as NRG-1 and VAMP-1, the former being a strong candidate susceptibility gene for schizophrenia. In the absence of frank neuronal loss in schizophrenia, restoration of neuronal and synaptic functions by atypical antipsychotics in the brains of schizophrenics maybe a key mechanism of therapeutic efficacy by re-establishing normal connectivity and functioning.

Antipsychotic treatment and neuregulin 1–ErbB4 signalling in schizophrenia

“…Additionally, in a clinical study, after a 2-week treatment with risperidone and quetiapine, NRG1 mRNA expression of PBLs of first-onset schizophrenia patients (who has not take antipsychotics before) significantly increased compared to the levels before antipsychotic drug therapies (Zhang et al, 2008). Moreover, an in vitro study has shown that NRG1 protein expression increased in human fetal brain aggregates after being exposed to clozapine for three weeks; however, the expression of NRG1 proteins did not change following exposure to haloperidol (Chana et al, 2009). In addition to the finding that NRG1-induced ErbB4 activation was significantly enhanced in the PFC of schizophrenia patients (Hahn et al, 2006), it is very interesting that NRG1-induced ErbB4 activation was significantly reduced by a 12-weeks treatment with haloperidol in mouse brains (Hahn et al, 2006).…”

Differential effects of short- and long-term antipsychotic treatment on the expression of neuregulin-1 and ErbB4 receptors in the rat brain

“…Evidence from the present and previous studies reveals that various antipsychotics with various pharmacological binding profiles regulate NRG1-ErbB4 expression in distinct ways (Chana et al, 2009;Wang et al, 2008;Zhang et al, 2008). There is no evidence that antipsychotics could directly bind with ErbB4 receptors, although they do possess affinities for several G-protein coupled receptors (GPCRs), particularly dopamine D 2 receptors and serotonin 5-HT receptors (Correll, 2010;Kapur and Mamo, 2003).…”

“…upregulated NRG1 and ErbB4 expression in the hippocampus, but had no effect on expression in the PFC of rats (Wang et al, 2008). An in vitro study demonstrated that exposure to clozapine (but not haloperidol) for three weeks promoted NRG1 protein expression in human fetal brain aggregates (Chana et al, 2009). Differential effects of antipsychotic treatment in the expression of NRG1 have also been observed in blood samples.…”

“…Several studies have investigated the effects of some antipsychotics on the expression of NRG1 and ErbB4 receptors, however, those results were discrepant (Chana et al, 2009;Shibuya et al, 2010;Wang et al, 2008;Zhang et al, 2008). A previous study found that 4-week treatment with clozapine (10mg/kg, once/day, i.p.)…”

“…These reports suggest that antipsychotic drugs may exert their therapeutic effects partially through the NRG1-ErbB4 signalling pathway. Several studies have investigated the effects of particular antipsychotics (haloperidol, clozapine and risperidone) on the expression of NRG1 and ErbB4 receptors in the brain, however, the results are inconsistent (Chana et al, 2009;Hahn et al, 2006;Wang et al, 2008). A key issue is that schizophrenia patients often undergo chronic, even life-time, antipsychotic treatment; therefore, this study investigated the effects of chronic (12 weeks) antipsychotic treatment on the expression of NRG1 and ErbB4 receptors, particularly treatment with olanzapine and aripiprazole, whose effects have not previously been examined.…”