- Email: [email protected]
SNARE Complex Dysfunction: A Unifying Hypothesis for Schizophrenia
Commentary
Biological Psychiatry
SNARE Complex Dysfunction: A Unifying Hypothesis for Schizophrenia Sara Marie Katrancha and Anthony J. Koleske Schizophrenia is a debilitating psychiatric disorder that affects approximately 1% of the world’s population at tremendous personal, social, and economic costs. Individuals with schizophrenia exhibit diverse combinations of positive, negative, and cognitive symptoms. Genetic susceptibility and environmental stressors are major risk factors for schizophrenia, contributing to the variety of phenotypes. It has been widely hypothesized that deficiencies in neurotransmitter systems contribute to schizophrenia. The dopamine hypothesis was supported by observations that pharmacologically increasing dopamine (e.g., with amphetamine) can induce psychosis in humans, whereas antipsychotics that block dopamine alleviate the positive symptoms of schizophrenia. Similarly, the glutamate hypothesis arose from observations that schizophrenia was associated with decreased glutamate levels, and the administration of glutamate antagonists in healthy subjects induced psychosis. These two hypotheses are combined in a third hypothesis, the synaptic hypothesis, which proposes that general deficits in synaptic function are a root cause of schizophrenia (1). In this issue of Biological Psychiatry, Ramos-Miguel et al. (2) explore the hypothesis that presynaptic abnormalities in the neurotransmitter exocytic machinery are altered in schizophrenia. This hypothesis is intriguing because altered neurotransmitter release could yield problems with dopamine and glutamate signaling, synapse function, and neural development, all of which have been observed in individuals with schizophrenia. Neurotransmitter release involves coordinated, dynamic interactions of multiple proteins that dock the neurotransmitter-containing vesicle to the plasma membrane at the release site and mediate membrane fusion. A complex of soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins lies at the heart of these events. Most neuronal SNARE complexes are composed of the vesicle SNARE protein synaptobrevin/vesicle-associated membrane protein and the target SNARE proteins syntaxin 1 and synaptosomal-associated protein 25 (SNAP25). These SNARE proteins interact via their α-helical SNARE motifs to form a four-helix bundle, of which two helices are contributed by SNAP25 and one each by syntaxin 1 and synaptobrevin (3– 5). Initial SNARE complex interaction occurs in trans, with the vesicle and plasma membranes tightly apposed. In this trans complex, the synaptobrevin transmembrane domain is anchored in the vesicle membrane, and the SNAP25 and syntaxin 1 transmembrane domains are anchored in the plasma membrane. The SNARE complex bundle in this trans state is only partially assembled. Zippering of the SNARE complex bundle is believed to provide the force for lipid mixing, which mediates membrane fusion and results in all
three SNARE protein transmembrane domains embedded in the same membrane, creating a cis complex. Although the three purified SNARE proteins are sufficient to mediate membrane fusion in vitro, many accessory proteins facilitate and regulate this process in vivo. For example, Munc18-1 is recruited to the SNARE complex through interactions with syntaxin 1 to promote SNARE complex formation and synaptic vesicle fusion (3–6). Neurotransmitter release is tightly regulated by calcium influx through voltage-gated calcium channels. In particular, calcium binding to synaptotagmin promotes the zippering of the four α-helical SNARE motifs from the loose trans-SNARE complex to a tight cisSNARE complex, facilitating lipid mixing, membrane fusion, and fusion pore formation (3–5). These actions are aided by complexins (1 and 2), which interact with synaptotagmin to prime synaptic vesicles and prepare the vesicles to form a fusion pore rapidly in response to calcium influx. Studies of animal models with alterations in the neurotransmitter release machinery support a role for altered neuroexocytosis in schizophrenia-related endophenotypes. The blind/drunk (Bdr) mouse model contains a dominant point mutation in SNAP25 that promotes increased formation and stability of the SNARE complex. The Bdr mouse shows impaired sensorimotor gating, similar to individuals with schizophrenia, in a prepulse inhibition startle response paradigm (7). These deficits are exacerbated by prenatal stress and almost completely rescued with the antipsychotic clozapine (8). In addition, the Bdr mouse shows negative endophenotypes, such as anxiety-related and apathetic behavior, some of which are also exacerbated by prenatal stress (7,8). A transgenic mouse that overexpresses Munc18-1 in the brain also exhibits schizophrenia-related endophenotypes, including anxiety-related behavior, impaired social interaction, increased sensitivity to hallucinogens, and sensorimotor gating deficits that can be rescued with clozapine (9). These mouse models suggest that modest changes in SNARE complex proteins or their regulators cause schizophrenia-related endophenotypes, which can be exacerbated by environmental stressors and rescued by antipsychotic treatment. In contrast to studies in mouse models, human genetic association studies have shown only nonreproducible, conflicting, or weak associations of genetic variations in SNARE proteins (syntaxin 1 and SNAP25) and accessory proteins (complexin and synaptotagmin) with schizophrenia (1). The best evidence for changes in neurotransmitter vesicle release machinery in schizophrenia has come from postmortem biochemical studies of human brains. In particular, syntaxin 1 phosphorylation, which promotes SNARE complex assembly (5), is decreased in schizophrenia. A reduction in
SEE CORRESPONDING ARTICLE ON PAGE 361
356 & 2015 Society of Biological Psychiatry Biological Psychiatry September 15, 2015; 78:356–358 www.sobp.org/journal
http://dx.doi.org/10.1016/j.biopsych.2015.07.013 ISSN: 0006-3223
Biological Psychiatry
Commentary
phospho-syntaxin 1 is believed to decrease SNARE complex formation and the association of syntaxin 1 with SNAP25 or Munc18-1. Antipsychotic treatment may reverse this deficit by increasing the reduced phospho-syntaxin 1 levels (6). Additional studies have reported changes in SNARE complex formation and syntaxin 1, Munc18-1, complexin, and SNAP25 levels related to schizophrenia, antipsychotic treatment, or both (1,10). These and other biochemical studies have quantified SNARE complexes, which are resistant to sodium dodecyl sulfate (SDS) denaturation, and carefully measured levels of individual SNARE proteins and accessory molecules by SDS polyacrylamide gel electrophoresis (PAGE). However, SDS treatment removes accessory binding partners, keeping only the main SNARE heterotrimer intact, which precludes the study of larger complexes containing SNARE proteins and accessory molecules. The study by Ramos-Miguel et al. (2) uses blue native (BN) PAGE to characterize the distribution of SNARE proteins and accessory molecules among complexes isolated from postmortem brain samples of individuals with schizophrenia and matched control subjects. This technique maintains proteins in their native conformations to facilitate analysis of accessory protein interactions that would have otherwise been unobservable. Using this technique, the authors were able to determine that SNARE protein–containing complexes are more abundant in the brains of individuals with schizophrenia. Ramos-Miguel et al. first observed increased amounts of syntaxin 1, Munc18-1, and complexin 1 associated with SNAP25 immunoprecipitate isolated from the orbitofrontal cortex of individuals with schizophrenia compared with matched control subjects. The authors then used BN-PAGE to measure the relative amounts and characterize the subunit composition of SNARE complexes in the same postmortem brain samples. Using this approach, the authors identified a 150-kDa SNARE complex containing synaptobrevin, SNAP25, syntaxin 1, and possibly Munc18-1 as well as a 200-kDa SNARE complex that additionally contained complexin 1. Both complexes were upregulated in schizophrenia. In addition, they observed reduced amounts of a 70-kDa SNAP25-synaptobrevin dimer and a 550-kDa multimer containing complexin 1 in schizophrenia, suggesting that SNARE proteins have a higher affinity for the accessory protein-containing complexes in schizophrenia. To probe possible factors controlling SNARE complex formation further, the authors treated the complexes with phosphatase to test the impact of phosphorylation on SNARE complex levels and composition. Phosphatase treatment led to decreased levels of complexin 1 in the 550-kDa multimer but increased levels of the 200-kDa complex, suggesting that dephosphorylation may result in the redistribution of complexin 1 from the 550-kDa multimer to the 150kDa SNARE complex (2). Together, these data suggest that the association of Munc18-1 and complexin 1 with SNARE proteins is increased in the brains of individuals with schizophrenia and regulated by protein phosphorylation. It is unclear whether the increased levels of SDS-resistant SNARE complexes observed in previous studies of schizophrenic brain are already fused vesicles (cis-SNARE complexes), prefusion vesicles (trans-SNARE complexes), or both. Ramos-Miguel et al. showed that the SNARE protein–
containing 150-kDa complex could be dissociated by SDS, suggesting that there are distinct SDS-resistant and SDSsensitive SNARE complexes. The 150-kDa complex was also disrupted by myricetin, which binds in the partially zippered trans-SNARE complex, suggesting that the 150-kDa complex is in the prefusion state. Based on this evidence, the authors hypothesize that SDS-resistant complexes represent tight cisSNARE complexes, whereas BN-PAGE provides a method to examine the understudied trans-SNARE complexes (2). Overall, this article establishes, in a replicable manner, that the upregulated formation of SNARE complexes and the abnormal expression of SNARE proteins and accessory molecules in a specific region (orbitofrontal cortex) of the human brain are associated with schizophrenia. Combined with a wealth of previous biochemical data in the field, the study suggests that schizophrenia involves increased steadystate levels of a 150-kDa complex of Munc18-1, syntaxin 1, synaptobrevin, and SNAP25 involved in vesicle docking and a 200-kDa complex additionally containing complexin 1 involved in synaptic vesicle priming. More definitive evidence linking genetic variation in the SNARE complex to schizophrenia would lend credence to the model that altered SNARE complex function is causative for the disease rather than a compensatory change resulting from disease-associated pathology or the effects of antipsychotic treatment. In addition, it is important to elucidate how SNARE proteins are altered in schizophrenia and if SNARE protein dysfunction occurs in most cases of schizophrenia. If SNARE protein dysfunction is common to individuals with schizophrenia regardless of their specific genetic insult, neurotransmitter release machinery may represent a promising target for therapeutic intervention, as alterations in these proteins impact glutamatergic signaling, dopaminergic signaling, and overall synaptic function.
Acknowledgments and Disclosures This work was supported by National Institutes of Health Grant Nos. CA133346 (AJK), GM100411 (AJK and T. Boggon), NS089662 (AJK and J. Grutzendler), and NS089439 (AJK and T. Pollard) and a pilot grant from the Stanley Center for Psychiatric Research. The authors report no biomedical financial interests or potential conflicts of interest.
Article Information From the Interdepartmental Neuroscience Program (SMK, AJK) and Departments of Molecular Biophysics and Biochemistry (SMK, AJK) and Neurobiology (AJK), Yale University, New Haven, Connecticut. Address correspondence to Anthony J. Koleske, Ph.D., Department of Molecular Biophysics and Biochemistry, Yale University, 333 Cedar Street, Sterling Hall of Medicine, CE-33, New Haven, CT 06420-8024; E-mail: [email protected]. Received Jul 16, 2015; accepted Jul 24, 2015.
References 1.
2.
Johnson RD, Oliver PL, Davies KE (2008): SNARE proteins and schizophrenia: Linking synaptic and neurodevelopmental hypotheses. Acta Biochim Pol 55:619–628. Ramos-Miguel A, Beasley CL, Dwork AJ, Mann JJ, Rosoklija G, Barr AM, et al. (2015): Increased SNARE protein-protein interactions in orbitofrontal and anterior cingulate cortices in schizophrenia. Biol Psychiatry 78:361–373.
Biological Psychiatry September 15, 2015; 78:356–358 www.sobp.org/journal
357
Biological Psychiatry
Commentary
3. 4. 5. 6.
7.
358
Sü dhof TC (2013): Neurotransmitter release: The last millisecond in the life of a synaptic vesicle. Neuron 80:675–690. Sü dhof TC,, Rothman JE (2009): Membrane fusion: Grappling with SNARE and SM proteins. Science 323:474–477. Snyder DA, Kelly ML, Woodbury DJ (2006): SNARE complex regulation by phosphorylation. Cell Biochem Biophys 45:111–123. Castillo MA, Ghose S, Tamminga CA, Ulery-Reynolds PG (2010): Deficits in syntaxin 1 phosphorylation in schizophrenia prefrontal cortex. Biol Psychiatry 67:208–216. Jeans AF, Oliver PL, Johnson R, Capogna M, Vikman J, Molnár Z, et al. (2007): A dominant mutation in Snap25 causes impaired vesicle trafficking, sensorimotor gating, and ataxia in the blind-drunk mouse. Proc Natl Acad Sci U S A 104:2431–2436.
8.
9.
10.
Oliver PL, Davies KE (2009): Interaction between environmental and genetic factors modulates schizophrenic endophenotypes in the Snap-25 mouse mutant blind-drunk. Hum Mol Genet 18: 4576–4589. Urigü en L, Gil-Pisa I, Munarriz-Cuezva E, Berrocoso E, Pascau J, SotoMontenegro ML, et al. (2013): Behavioral, neurochemical and morphological changes induced by the overexpression of munc18-1a in brain of mice: Relevance to schizophrenia. Transl Psychiatry 3:e221. Gil-Pisa I, Munarriz-Cuezva E, Ramos-Miguel A, Urigü en L, Meana JJ, García-Sevilla JA (2012): Regulation of munc18-1 and syntaxin-1A interactive partners in schizophrenia prefrontal cortex: Downregulation of munc18-1a isoform and 75 kDa SNARE complex after antipsychotic treatment. Int J Neuropsychopharmacol 15:573–588.
Biological Psychiatry September 15, 2015; 78:356–358 www.sobp.org/journal
Biological Psychiatry
SNARE Complex Dysfunction: A Unifying Hypothesis for Schizophrenia Sara Marie Katrancha and Anthony J. Koleske Schizophrenia is a debilitating psychiatric disorder that affects approximately 1% of the world’s population at tremendous personal, social, and economic costs. Individuals with schizophrenia exhibit diverse combinations of positive, negative, and cognitive symptoms. Genetic susceptibility and environmental stressors are major risk factors for schizophrenia, contributing to the variety of phenotypes. It has been widely hypothesized that deficiencies in neurotransmitter systems contribute to schizophrenia. The dopamine hypothesis was supported by observations that pharmacologically increasing dopamine (e.g., with amphetamine) can induce psychosis in humans, whereas antipsychotics that block dopamine alleviate the positive symptoms of schizophrenia. Similarly, the glutamate hypothesis arose from observations that schizophrenia was associated with decreased glutamate levels, and the administration of glutamate antagonists in healthy subjects induced psychosis. These two hypotheses are combined in a third hypothesis, the synaptic hypothesis, which proposes that general deficits in synaptic function are a root cause of schizophrenia (1). In this issue of Biological Psychiatry, Ramos-Miguel et al. (2) explore the hypothesis that presynaptic abnormalities in the neurotransmitter exocytic machinery are altered in schizophrenia. This hypothesis is intriguing because altered neurotransmitter release could yield problems with dopamine and glutamate signaling, synapse function, and neural development, all of which have been observed in individuals with schizophrenia. Neurotransmitter release involves coordinated, dynamic interactions of multiple proteins that dock the neurotransmitter-containing vesicle to the plasma membrane at the release site and mediate membrane fusion. A complex of soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins lies at the heart of these events. Most neuronal SNARE complexes are composed of the vesicle SNARE protein synaptobrevin/vesicle-associated membrane protein and the target SNARE proteins syntaxin 1 and synaptosomal-associated protein 25 (SNAP25). These SNARE proteins interact via their α-helical SNARE motifs to form a four-helix bundle, of which two helices are contributed by SNAP25 and one each by syntaxin 1 and synaptobrevin (3– 5). Initial SNARE complex interaction occurs in trans, with the vesicle and plasma membranes tightly apposed. In this trans complex, the synaptobrevin transmembrane domain is anchored in the vesicle membrane, and the SNAP25 and syntaxin 1 transmembrane domains are anchored in the plasma membrane. The SNARE complex bundle in this trans state is only partially assembled. Zippering of the SNARE complex bundle is believed to provide the force for lipid mixing, which mediates membrane fusion and results in all
three SNARE protein transmembrane domains embedded in the same membrane, creating a cis complex. Although the three purified SNARE proteins are sufficient to mediate membrane fusion in vitro, many accessory proteins facilitate and regulate this process in vivo. For example, Munc18-1 is recruited to the SNARE complex through interactions with syntaxin 1 to promote SNARE complex formation and synaptic vesicle fusion (3–6). Neurotransmitter release is tightly regulated by calcium influx through voltage-gated calcium channels. In particular, calcium binding to synaptotagmin promotes the zippering of the four α-helical SNARE motifs from the loose trans-SNARE complex to a tight cisSNARE complex, facilitating lipid mixing, membrane fusion, and fusion pore formation (3–5). These actions are aided by complexins (1 and 2), which interact with synaptotagmin to prime synaptic vesicles and prepare the vesicles to form a fusion pore rapidly in response to calcium influx. Studies of animal models with alterations in the neurotransmitter release machinery support a role for altered neuroexocytosis in schizophrenia-related endophenotypes. The blind/drunk (Bdr) mouse model contains a dominant point mutation in SNAP25 that promotes increased formation and stability of the SNARE complex. The Bdr mouse shows impaired sensorimotor gating, similar to individuals with schizophrenia, in a prepulse inhibition startle response paradigm (7). These deficits are exacerbated by prenatal stress and almost completely rescued with the antipsychotic clozapine (8). In addition, the Bdr mouse shows negative endophenotypes, such as anxiety-related and apathetic behavior, some of which are also exacerbated by prenatal stress (7,8). A transgenic mouse that overexpresses Munc18-1 in the brain also exhibits schizophrenia-related endophenotypes, including anxiety-related behavior, impaired social interaction, increased sensitivity to hallucinogens, and sensorimotor gating deficits that can be rescued with clozapine (9). These mouse models suggest that modest changes in SNARE complex proteins or their regulators cause schizophrenia-related endophenotypes, which can be exacerbated by environmental stressors and rescued by antipsychotic treatment. In contrast to studies in mouse models, human genetic association studies have shown only nonreproducible, conflicting, or weak associations of genetic variations in SNARE proteins (syntaxin 1 and SNAP25) and accessory proteins (complexin and synaptotagmin) with schizophrenia (1). The best evidence for changes in neurotransmitter vesicle release machinery in schizophrenia has come from postmortem biochemical studies of human brains. In particular, syntaxin 1 phosphorylation, which promotes SNARE complex assembly (5), is decreased in schizophrenia. A reduction in
SEE CORRESPONDING ARTICLE ON PAGE 361
356 & 2015 Society of Biological Psychiatry Biological Psychiatry September 15, 2015; 78:356–358 www.sobp.org/journal
http://dx.doi.org/10.1016/j.biopsych.2015.07.013 ISSN: 0006-3223
Biological Psychiatry
Commentary
phospho-syntaxin 1 is believed to decrease SNARE complex formation and the association of syntaxin 1 with SNAP25 or Munc18-1. Antipsychotic treatment may reverse this deficit by increasing the reduced phospho-syntaxin 1 levels (6). Additional studies have reported changes in SNARE complex formation and syntaxin 1, Munc18-1, complexin, and SNAP25 levels related to schizophrenia, antipsychotic treatment, or both (1,10). These and other biochemical studies have quantified SNARE complexes, which are resistant to sodium dodecyl sulfate (SDS) denaturation, and carefully measured levels of individual SNARE proteins and accessory molecules by SDS polyacrylamide gel electrophoresis (PAGE). However, SDS treatment removes accessory binding partners, keeping only the main SNARE heterotrimer intact, which precludes the study of larger complexes containing SNARE proteins and accessory molecules. The study by Ramos-Miguel et al. (2) uses blue native (BN) PAGE to characterize the distribution of SNARE proteins and accessory molecules among complexes isolated from postmortem brain samples of individuals with schizophrenia and matched control subjects. This technique maintains proteins in their native conformations to facilitate analysis of accessory protein interactions that would have otherwise been unobservable. Using this technique, the authors were able to determine that SNARE protein–containing complexes are more abundant in the brains of individuals with schizophrenia. Ramos-Miguel et al. first observed increased amounts of syntaxin 1, Munc18-1, and complexin 1 associated with SNAP25 immunoprecipitate isolated from the orbitofrontal cortex of individuals with schizophrenia compared with matched control subjects. The authors then used BN-PAGE to measure the relative amounts and characterize the subunit composition of SNARE complexes in the same postmortem brain samples. Using this approach, the authors identified a 150-kDa SNARE complex containing synaptobrevin, SNAP25, syntaxin 1, and possibly Munc18-1 as well as a 200-kDa SNARE complex that additionally contained complexin 1. Both complexes were upregulated in schizophrenia. In addition, they observed reduced amounts of a 70-kDa SNAP25-synaptobrevin dimer and a 550-kDa multimer containing complexin 1 in schizophrenia, suggesting that SNARE proteins have a higher affinity for the accessory protein-containing complexes in schizophrenia. To probe possible factors controlling SNARE complex formation further, the authors treated the complexes with phosphatase to test the impact of phosphorylation on SNARE complex levels and composition. Phosphatase treatment led to decreased levels of complexin 1 in the 550-kDa multimer but increased levels of the 200-kDa complex, suggesting that dephosphorylation may result in the redistribution of complexin 1 from the 550-kDa multimer to the 150kDa SNARE complex (2). Together, these data suggest that the association of Munc18-1 and complexin 1 with SNARE proteins is increased in the brains of individuals with schizophrenia and regulated by protein phosphorylation. It is unclear whether the increased levels of SDS-resistant SNARE complexes observed in previous studies of schizophrenic brain are already fused vesicles (cis-SNARE complexes), prefusion vesicles (trans-SNARE complexes), or both. Ramos-Miguel et al. showed that the SNARE protein–
containing 150-kDa complex could be dissociated by SDS, suggesting that there are distinct SDS-resistant and SDSsensitive SNARE complexes. The 150-kDa complex was also disrupted by myricetin, which binds in the partially zippered trans-SNARE complex, suggesting that the 150-kDa complex is in the prefusion state. Based on this evidence, the authors hypothesize that SDS-resistant complexes represent tight cisSNARE complexes, whereas BN-PAGE provides a method to examine the understudied trans-SNARE complexes (2). Overall, this article establishes, in a replicable manner, that the upregulated formation of SNARE complexes and the abnormal expression of SNARE proteins and accessory molecules in a specific region (orbitofrontal cortex) of the human brain are associated with schizophrenia. Combined with a wealth of previous biochemical data in the field, the study suggests that schizophrenia involves increased steadystate levels of a 150-kDa complex of Munc18-1, syntaxin 1, synaptobrevin, and SNAP25 involved in vesicle docking and a 200-kDa complex additionally containing complexin 1 involved in synaptic vesicle priming. More definitive evidence linking genetic variation in the SNARE complex to schizophrenia would lend credence to the model that altered SNARE complex function is causative for the disease rather than a compensatory change resulting from disease-associated pathology or the effects of antipsychotic treatment. In addition, it is important to elucidate how SNARE proteins are altered in schizophrenia and if SNARE protein dysfunction occurs in most cases of schizophrenia. If SNARE protein dysfunction is common to individuals with schizophrenia regardless of their specific genetic insult, neurotransmitter release machinery may represent a promising target for therapeutic intervention, as alterations in these proteins impact glutamatergic signaling, dopaminergic signaling, and overall synaptic function.
Acknowledgments and Disclosures This work was supported by National Institutes of Health Grant Nos. CA133346 (AJK), GM100411 (AJK and T. Boggon), NS089662 (AJK and J. Grutzendler), and NS089439 (AJK and T. Pollard) and a pilot grant from the Stanley Center for Psychiatric Research. The authors report no biomedical financial interests or potential conflicts of interest.
Article Information From the Interdepartmental Neuroscience Program (SMK, AJK) and Departments of Molecular Biophysics and Biochemistry (SMK, AJK) and Neurobiology (AJK), Yale University, New Haven, Connecticut. Address correspondence to Anthony J. Koleske, Ph.D., Department of Molecular Biophysics and Biochemistry, Yale University, 333 Cedar Street, Sterling Hall of Medicine, CE-33, New Haven, CT 06420-8024; E-mail: [email protected]. Received Jul 16, 2015; accepted Jul 24, 2015.
References 1.
2.
Johnson RD, Oliver PL, Davies KE (2008): SNARE proteins and schizophrenia: Linking synaptic and neurodevelopmental hypotheses. Acta Biochim Pol 55:619–628. Ramos-Miguel A, Beasley CL, Dwork AJ, Mann JJ, Rosoklija G, Barr AM, et al. (2015): Increased SNARE protein-protein interactions in orbitofrontal and anterior cingulate cortices in schizophrenia. Biol Psychiatry 78:361–373.
Biological Psychiatry September 15, 2015; 78:356–358 www.sobp.org/journal
357
Biological Psychiatry
Commentary
3. 4. 5. 6.
7.
358
Sü dhof TC (2013): Neurotransmitter release: The last millisecond in the life of a synaptic vesicle. Neuron 80:675–690. Sü dhof TC,, Rothman JE (2009): Membrane fusion: Grappling with SNARE and SM proteins. Science 323:474–477. Snyder DA, Kelly ML, Woodbury DJ (2006): SNARE complex regulation by phosphorylation. Cell Biochem Biophys 45:111–123. Castillo MA, Ghose S, Tamminga CA, Ulery-Reynolds PG (2010): Deficits in syntaxin 1 phosphorylation in schizophrenia prefrontal cortex. Biol Psychiatry 67:208–216. Jeans AF, Oliver PL, Johnson R, Capogna M, Vikman J, Molnár Z, et al. (2007): A dominant mutation in Snap25 causes impaired vesicle trafficking, sensorimotor gating, and ataxia in the blind-drunk mouse. Proc Natl Acad Sci U S A 104:2431–2436.
8.
9.
10.
Oliver PL, Davies KE (2009): Interaction between environmental and genetic factors modulates schizophrenic endophenotypes in the Snap-25 mouse mutant blind-drunk. Hum Mol Genet 18: 4576–4589. Urigü en L, Gil-Pisa I, Munarriz-Cuezva E, Berrocoso E, Pascau J, SotoMontenegro ML, et al. (2013): Behavioral, neurochemical and morphological changes induced by the overexpression of munc18-1a in brain of mice: Relevance to schizophrenia. Transl Psychiatry 3:e221. Gil-Pisa I, Munarriz-Cuezva E, Ramos-Miguel A, Urigü en L, Meana JJ, García-Sevilla JA (2012): Regulation of munc18-1 and syntaxin-1A interactive partners in schizophrenia prefrontal cortex: Downregulation of munc18-1a isoform and 75 kDa SNARE complex after antipsychotic treatment. Int J Neuropsychopharmacol 15:573–588.
Biological Psychiatry September 15, 2015; 78:356–358 www.sobp.org/journal