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 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.

• Authors: Gursharan Chana, Ginger Lucero, Shahid Salaria, Jean Lozach, Pinyi Du, Christopher Woelk, Ian Everall
• Journal: Schizophrenia research (Schizophr Res) Vol. 113 Issue 2-3 Pg. 273-6 (Sep 2009) ISSN: 1573-2509 [Electronic] Netherlands
• PMID: 19502011 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Antipsychotic Agents
• Neuregulin-1
• Vesicle-Associated Membrane Protein 1
• Clozapine
• Haloperidol

Topics

• Antipsychotic Agents (pharmacology)
• Brain (drug effects, embryology)
• Clozapine (pharmacology)
• Fetus
• Haloperidol (pharmacology)
• Humans
• Neuregulin-1 (genetics, metabolism)
• Up-Regulation (drug effects)
• Vesicle-Associated Membrane Protein 1 (genetics, metabolism)