title: 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.affiliation: Department of Psychiatry, University of California San Diego, La Jolla, CA 92093-0603, USA. gchana@ucsd.edu
authors.forename: Gursharan
authors.initials: G
authors.lastname: Chana
authors.forename: Ginger
authors.initials: G
authors.lastname: Lucero
authors.forename: Shahid
authors.initials: S
authors.lastname: Salaria
authors.forename: Jean
authors.initials: J
authors.lastname: Lozach
authors.forename: Pinyi
authors.initials: P
authors.lastname: Du
authors.forename: Christopher
authors.initials: C
authors.lastname: Woelk
authors.forename: Ian
authors.initials: I
authors.lastname: Everall
mesh_terms: D014150:Antipsychotic Agents / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects* / Q000196:embryology; D003024:Clozapine / Q000494:pharmacology*; D005333:Fetus; D006220:Haloperidol / Q000494:pharmacology; D006801:Humans; D020890:Neuregulin-1 / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects*; D050987:Vesicle-Associated Membrane Protein 1 / Q000235:genetics / Q000378:metabolism*
chemical_list: D014150:Antipsychotic Agents; D020890:Neuregulin-1; D050987:Vesicle-Associated Membrane Protein 1; D003024:Clozapine; D006220:Haloperidol