Munc18-1 and syntaxin-1 are crucial interacting molecules for synaptic membrane fusion and neurotransmitter release. Contrasting abnormalities of several proteins of the exocytotic machinery, including the formation of SNARE (synaptobrevin, SNAP-25 and syntaxin-1) complexes, have been reported in schizophrenia. This study quantified in the dorsolateral prefrontal cortex (PFC, Brodmann area 9) the immunocontent of munc18-1a/b isoforms, syntaxin-1A, other presynaptic proteins (synaptotagmin, synaptophysin), and SNARE complexes, as well as the effects of psychoactive drug exposure, in schizophrenia (SZ, n=24), non-schizophrenia suicide (SD, n=13) and major depression (MD, n=15) subjects compared to matched controls (n=39). SZ was associated with normal expression of munc18-1a/b and increased syntaxin-1A (+44%). The presence of antipsychotic drugs reduced the basal content of munc18-1a isoform (-23%) and synaptobrevin (-32%), and modestly reduced that of up-regulated syntaxin-1A (-16%). Munc18-1a and syntaxin-1A protein expression correlated positively in controls but showed a markedly opposite pattern in SZ, regardless of antipsychotic treatment. Thus, the ratio of syntaxin-1A to munc18-1a showed a net increase in SZ (+53/114%). The SNARE complex (75 kDa) was found unaltered in antipsychotic-free and reduced (-28%) in antipsychotic-treated SZ subjects. None of these abnormalities were observed in SD and MD subjects, unexposed or exposed to psychoactive drugs. The results reveal some exocytotic dysfunctions in SZ that are probably related to an imbalance of the interaction between munc18-1a and SNARE (mainly syntaxin-1A) complex. Moreover, antipsychotic drug treatment is associated with lower content of key proteins of the exocytotic machinery, which could result in a destabilization/impairment of neurosecretion.
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 D1 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. The animal could provide valuable insights into phenotypic aspects of this psychiatric disorder.
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