Behavioral, neurochemical and morphological changes induced by the overexpression of munc18-1a in brain of mice: relevance to schizophrenia

Overexpression of the mammalian homolog of the unc-18 gene (munc18-1) has been described in the brain of subjects with schizophrenia. Munc18-1 protein is involved in membrane fusion processes, exocytosis and neurotransmitter release. A transgenic mouse strain that overexpresses the protein isoform munc18-1a in the brain was characterized. This animal displays several schizophrenia-related behaviors, supersensitivity to hallucinogenic drugs and deficits in prepulse inhibition that reverse after antipsychotic treatment. Relevant brain areas (that is, cortex and striatum) exhibit reduced expression of dopamine D-1 receptors and dopamine transporters together with enhanced amphetamine-induced in vivo dopamine release. Magnetic resonance imaging demonstrates decreased gray matter volume in the transgenic animal. In conclusion, the mouse overexpressing brain munc18-1a represents a new valid animal model that resembles functional and structural abnormalities in patients with schizophrenia.Brainco Biopharma SL; Centro de Investigacion Biomedica en Red de Salud Mental; Instituto de Salud Carlos III (CIBERSAM); Spanish MICINN; FEDER SAF2009-08460, SAF2010-21948,AGL2009-11358, SAF2011-29918, PI10/02986, CP08/00017,CEN-20101014; Basque Government PR10UN01 IT-199/07; University of the Basque Country (UPV/EHU); Complutense University of Madrid UCM GR42/10-96207