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.