title: Regulation of munc18-1 and syntaxin-1A interactive partners in schizophrenia prefrontal cortex: down-regulation of munc18-1a isoform and 75 kDa SNARE complex after antipsychotic treatment.
abstract: 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.
authors.affiliation: Laboratorio de Neurofarmacología, IUNICS, Universitat de les Illes Balears and Red Temática de Investigación Cooperativa en Salud-RETICS-RTA, Palma de Mallorca, Spain.
authors.forename: Itziar
authors.initials: I
authors.lastname: Gil-Pisa
authors.forename: Eva
authors.initials: E
authors.lastname: Munarriz-Cuezva
authors.forename: Alfredo
authors.initials: A
authors.lastname: Ramos-Miguel
authors.forename: Leyre
authors.initials: L
authors.lastname: Urigüen
authors.forename: J Javier
authors.initials: JJ
authors.lastname: Meana
authors.forename: Jesús A
authors.initials: JA
authors.lastname: García-Sevilla
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000378:metabolism*; D003865:Major Depressive Disorder / Q000378:metabolism*; D015536:Down-Regulation; D005089:Exocytosis / Q000502:physiology; D006801:Humans; D008297:Male; D051938:Munc18 Proteins / Q000378:metabolism*; D017397:Prefrontal Cortex / Q000378:metabolism*; D020033:Protein Isoforms / Q000378:metabolism; D050683:R-SNARE Proteins / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D050600:SNARE Proteins / Q000378:metabolism*; D012559:Schizophrenia / Q000188:drug therapy / Q000378:metabolism; D013405:Suicide; D050857:Synaptotagmins / Q000378:metabolism; D050827:Syntaxin 1 / Q000378:metabolism*
chemical_list: D014150:Antipsychotic Agents; D051938:Munc18 Proteins; D020033:Protein Isoforms; D050683:R-SNARE Proteins; D050600:SNARE Proteins; D050827:Syntaxin 1; D050857:Synaptotagmins