title: Presynaptic proteins in the prefrontal cortex of patients with schizophrenia and rats with abnormal prefrontal development.
abstract: Dysfunction of the prefrontal cortex in schizophrenia may be associated with abnormalities in synaptic structure and/or function and reflected in altered concentrations of proteins in presynaptic terminals and involved in synaptic plasticity (synaptobrevin/ vesicle-associated membrane protein (VAMP), synaptosomal-associated protein-25 (SNAP-25), syntaxin, synaptophysin and growth-associated protein-43 (GAP-43)). We examined the immunoreactivity of these synapse-associated proteins via quantitative immunoblotting in the prefrontal cortex of patients with schizophrenia (n=18) and in normal controls (n=23). We also tested the stability of these proteins across successive post-mortem intervals in rat brains (at 0, 3, 12, 24, 48, and 70 h). To investigate whether experimental manipulation of prefrontal cortical development in the rat alters prefrontal synaptic protein levels, we lesioned the ventral hippocampus of rats on postnatal day 7 and measured immunoreactivity of presynaptic proteins in the prefrontal cortex on postnatal day 70. VAMP immunoreactivity was lower in the schizophrenic patients by 22% (P<0.03). There were no differences in the immunoreactivity of any other proteins measured in schizophrenic patients as compared to the matched controls. Proteins were fairly stable up to 24 h and thereafter the abundance of most proteins examined was significantly reduced (falling to as low as 20% of baseline levels at 48-70 h). VAMP immunoreactivity was higher in the lesioned rats as compared to sham controls by 22% (P&<0.03). There were no significant differences between the lesioned rats and sham animals in any other presynaptic protein. These data suggest that apparently profound prefrontal cortical dysfunction in schizophrenia, as well as in an animal model of schizophrenia, may exist without gross changes in the abundance of many synaptic proteins but discrete changes in selected presynaptic molecules may be present.
authors.affiliation: Clinical Brain Disorders Branch, Intramural Research Program, National Institutes of Mental Health, NIH, Bethesda, MD, USA.
authors.forename: N D
authors.initials: ND
authors.lastname: Halim
authors.forename: C S
authors.initials: CS
authors.lastname: Weickert
authors.forename: B W
authors.initials: BW
authors.lastname: McClintock
authors.forename: T M
authors.initials: TM
authors.lastname: Hyde
authors.forename: D R
authors.initials: DR
authors.lastname: Weinberger
authors.forename: J E
authors.initials: JE
authors.lastname: Kleinman
authors.forename: B K
authors.initials: BK
authors.lastname: Lipska
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D015415:Biomarkers / Q000032:analysis; D002352:Carrier Proteins / Q000032:analysis; D016022:Case-Control Studies; D004195:Disease Models, Animal; D005260:Female; D019922:GAP-43 Protein / Q000032:analysis; D006624:Hippocampus / Q000737:chemistry / Q000502:physiology; D006801:Humans; D008297:Male; D016555:Matched-Pair Analysis; D008565:Membrane Proteins / Q000032:analysis*; D008875:Middle Aged; D009415:Nerve Net / Q000737:chemistry; D009419:Nerve Tissue Proteins / Q000032:analysis*; D017397:Prefrontal Cortex / Q000002:abnormalities / Q000737:chemistry* / Q000503:physiopathology; D017729:Presynaptic Terminals / Q000737:chemistry*; D050765:Qa-SNARE Proteins; D050683:R-SNARE Proteins; D051381:Rats; D017207:Rats, Sprague-Dawley; D050600:SNARE Proteins; D012559:Schizophrenia / Q000503:physiopathology*; D016708:Synaptophysin / Q000032:analysis; D050825:Synaptosomal-Associated Protein 25; D033921:Vesicular Transport Proteins
chemical_list: D015415:Biomarkers; D002352:Carrier Proteins; D019922:GAP-43 Protein; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D050765:Qa-SNARE Proteins; D050683:R-SNARE Proteins; C494208:SNAP25 protein, human; D050600:SNARE Proteins; C494210:Snap25 protein, rat; D016708:Synaptophysin; D050825:Synaptosomal-Associated Protein 25; C114051:VAPA protein, human; C491919:Vapa protein, rat; D033921:Vesicular Transport Proteins