Synaptosomal-associated Protein 25kDa Research Articles

Allosteric inhibition of phosphodiesterase 4D induces biphasic memory-enhancing effects associated with learning-activated signaling pathways.

Phosphodiesterase 4D negative allosteric modulators (PDE4D NAMs) enhance memory and cognitive function in animal models without emetic-like side effects. However, the relationship between increased cyclic adenosine monophosphate (cAMP) signaling and the effects of PDE4D NAM remains elusive. To investigate the roles of hippocampal cAMP metabolism and synaptic activation in the effects of D159687, a PDE4D NAM, under baseline and learning-stimulated conditions. At 3mg/kg, D159687 enhanced memory formation and consolidation in contextual fear conditioning; however, neither lower (0.3mg/kg) nor higher (30mg/kg) doses induced memory-enhancing effects. A biphasic (bell-shaped) dose-response effect was also observed in a scopolamine-induced model of amnesia in the Y-maze, whereas D159687 dose-dependently caused an emetic-like effect in the xylazine/ketamine anesthesia test. At 3mg/kg, D159687 increased cAMP levels in the hippocampal CA1 region after conditioning in the fear conditioning test, but not in the home-cage or conditioning cage (i.e., context only). By contrast, 30mg/kg of D159687 increased hippocampal cAMP levels under all conditions. Although both 3 and 30mg/kg of D159687 upregulated learning-induced Fos expression in the hippocampal CA1 30min after conditioning, 3mg/kg, but not 30mg/kg, of D159687 induced phosphorylation of synaptic plasticity-related proteins such as cAMP-responsive element-binding protein, synaptosomal-associated protein 25kDa, and the N-methyl-D-aspartate receptor subunit NR2A. Our findings suggest that learning-stimulated conditions can alter the effects of a PDE4D NAM on hippocampal cAMP levels and imply that a PDE4D NAM exerts biphasic memory-enhancing effects associated with synaptic plasticity-related signaling activation.

Diagnostic Utility of Cerebrospinal Fluid Biomarkers in Patients with Rapidly Progressive Dementia.

This study was undertaken to apply established and emerging cerebrospinal fluid (CSF) biomarkers to improve diagnostic accuracy in patients with rapidly progressive dementia (RPD). Overlap in clinical presentation and results of diagnostic tests confounds etiologic diagnosis in patients with RPD. Objective measures are needed to improve diagnostic accuracy and to recognize patients with potentially treatment-responsive causes of RPD. Biomarkers of Alzheimer disease neuropathology (amyloid-β 42/40 ratio, phosphorylated tau [p-tau181, p-tau231]), neuroaxonal/neuronal injury (neurofilament light chain [NfL], visinin-like protein-1 [VILIP-1], total tau), neuroinflammation (chitinase-3-like protein [YKL-40], soluble triggering receptor expressed on myeloid cells 2 [sTREM2], glial fibrillary acidic protein [GFAP], monocyte chemoattractant protein-1 [MCP-1]), and synaptic dysfunction (synaptosomal-associated protein 25kDa, neurogranin) were measured in CSF obtained at presentation from 78 prospectively accrued patients with RPD due to neurodegenerative, vascular, and autoimmune/inflammatory diseases; 35 age- and sex-matched patients with typically progressive neurodegenerative disease; and 72 cognitively normal controls. Biomarker levels were compared across etiologic diagnoses, by potential treatment responsiveness, and between patients with typical and rapidly progressive presentations of neurodegenerative disease. Alzheimer disease biomarkers were associated with neurodegenerative causes of RPD. High NfL, sTREM2, and YKL-40 and low VILIP-1 identified patients with autoimmune/inflammatory diseases. MCP-1 levels were highest in patients with vascular causes of RPD. A multivariate model including GFAP, MCP-1, p-tau181, and sTREM2 identified the 44 patients with treatment-responsive causes of RPD with 89% accuracy. Minimal differences were observed between typical and rapidly progressive presentations of neurodegenerative disease. Selected CSF biomarkers at presentation were associated with etiologic diagnoses and treatment responsiveness in patients with heterogeneous causes of RPD. The ability of cross-sectional biomarkers to inform upon mechanisms that drive rapidly progressive neurodegenerative disease is less clear. ANN NEUROL 2024;95:299-313.

Evaluation of cerebrospinal fluid levels of synaptic vesicle protein, VAMP-2, across the sporadic Alzheimer’s disease continuum

BackgroundSynapse loss is an early event that precedes neuronal death and symptom onset and is considered the best neuropathological correlate of cognitive decline in Alzheimer’s disease (AD). Vesicle-associated membrane protein 2 (VAMP-2) has emerged as a promising biomarker of AD-related synapse degeneration in cerebrospinal fluid (CSF). The aim of this study was to explore the CSF profile of VAMP-2 across the AD continuum in relation to core AD biomarkers, other synaptic proteins, neurogranin (Ng) and synaptosomal-associated Protein-25 kDa (SNAP-25) and cognitive performance.MethodsWe developed a digital immunoassay on the Single Molecule Array platform to quantify VAMP-2 in CSF and used existing immunoassays to quantify Ng, SNAP-25 and core CSF AD biomarkers. The clinical study included 62 cognitively unimpaired AD biomarker-negative subjects and 152 participants across the AD continuum from the SPIN cohort (Sant Pau Initiative on Neurodegeneration). Cognitive measures of episodic, semantic, executive and visuospatial domains and global cognition were included. Statistical methods included χ2 tests, spearman correlation, and ANCOVA analyses.ResultsThe VAMP-2 assay had a good analytical performance (repeatability 8.9%, intermediate precision 10.3%). Assay antibodies detected native VAMP-2 protein in human brain homogenates. CSF concentrations of VAMP-2, neurogranin and SNAP-25 were lower in preclinical AD stage 1 compared to controls and higher at later AD stages compared to AD stage 1 and were associated with core AD biomarkers, particularly total tau (adj. r2 = 0.62 to 0.78, p < 0.001). All three synaptic proteins were associated with all cognitive domains in individuals on the AD continuum (adj. r2 = 0.04 to 0.19, p < 0.05).ConclusionsOur novel digital immunoassay accurately measures VAMP-2 changes in CSF, which reflect AD biomarkers and cognitive performance across multiple domains.

Botox (onabotulinumtoxinA) mechanism of action.

Studies in the 1920s found that botulinum neurotoxin type A (BoNT/A) inhibited the activity of motor and parasympathetic nerve endings, confirmed several decades later to be due to decreased acetylcholine release. The 1970s were marked by studies of cellular mechanisms aided by use of neutralizing antibodies as pharmacologic tools: BoNT/A disappeared from accessibility to neutralizing antibodies within minutes, although it took several hours for onset of muscle weakness. The multi-step mechanism was experimentally confirmed and is now recognized to consist broadly of binding to nerve terminals, internalization, and lysis or cleavage of a protein (SNAP-25: synaptosomal associated protein-25 kDa) that is part of the SNARE (Soluble NSF Attachment protein REceptor) complex needed for synaptic vesicle docking and fusion. Clinical use of the BoNT/A product onabotulinumtoxinA was based on its ability to reduce muscle contractions via inhibition of acetylcholine from motor terminals. Sensory mechanisms of onabotulinumtoxinA have now been identified, supporting its successful treatment of chronic migraine and urgency in overactive bladder. Exploration into migraine mechanisms led to anatomical studies documenting pain fibers that send axons through sutures of the skull to outside the head-a potential route by which extracranial injections could affect intracranial processes. Several clinical studies have also identified benefits of onabotulinumtoxinA in major depression, which have been attributed to central responses induced by feedback from facial muscle and skin movement. Overall, the history of BoNT/A is distinguished by basic science studies that stimulated clinical use and, conversely, clinical observations that spurred basic research into novel mechanisms of action.

OnabotulinumtoxinA effects on trigeminal nociceptors.

OnabotulinumtoxinA (onabotA) is approved globally for prevention of chronic migraine; however, the classical mechanism of action of onabotA in motor and autonomic neurons cannot fully explain the effectiveness of onabotulinumtoxinA in this sensory neurological disease. We sought to explore the direct effects of onabotulinumtoxinA on mouse trigeminal ganglion sensory neurons using an inflammatory soup-based model of sensitization. Primary cultured trigeminal ganglion neurons were pre-treated with inflammatory soup, then treated with onabotulinumtoxinA (2.75 pM). Treated neurons were used to examine transient receptor potential vanilloid subtype 1 and transient receptor potential ankyrin 1 cell-surface expression, calcium influx, and neuropeptide release. We found that onabotulinumtoxinA cleaved synaptosomal-associated protein-25 kDa in cultured trigeminal ganglion neurons; synaptosomal-associated protein-25 kDa cleavage was enhanced by inflammatory soup pre-treatment, suggesting greater uptake of toxin under sensitized conditions. OnabotulinumtoxinA also prevented inflammatory soup-mediated increases in TRPV1 and TRPA1 cell-surface expression, without significantly altering TRPV1 or TRPA1 protein expression in unsensitized conditions. We observed similar inhibitory effects of onabotulinumtoxinA on TRP-mediated calcium influx and TRPV1- and TRPA1-mediated release of calcitonin gene-related peptide and prostaglandin 2 under sensitized, but not unsensitized control, conditions. Our data deepen the understanding of the sensory mechanism of action of onabotulinumtoxinA and support the notion that, once endocytosed, the cytosolic light chain of onabotulinumtoxinA cleaves synaptosomal-associated protein-25 kDa to prevent soluble N-ethylmaleimide-sensitive factor attachment protein receptor-mediated processes more generally in motor, autonomic, and sensory neurons.

Synthesis of genetic association studies on autism spectrum disorders using a genetic model-free approach.

Autism spectrum disorder (ASD) is a clinically and genetically heterogeneous group of neurodevelopmental disorders. Despite the extensive efforts of scientists, the etiology of ASD is far from completely elucidated. In an effort to enlighten the genetic architecture of ASDs, a meta-analysis of all available genetic association studies (GAS) was conducted. We searched in the Human Genome Epidemiology Navigator (HuGE Navigator) and PubMed for available case-control GAS of ASDs. The threshold for meta-analysis was two studies per genetic variant. The association between genotype distribution and ASDs was examined using the generalized linear odds ratio (ORG). For variants with available allele frequencies, the examined model was the allele contrast. Overall, 57 candidate genes and 128 polymorphisms were investigated in 159 articles. In total 28 genetic polymorphisms have been shown to be associated with ASDs, that are harbored in 19 genes. Statistically significant results were revealed for the variants of the following genes adenosine deaminase (ADA), bone marrow stromal cell antigen-1 (CD157/BST1), Dopamine receptor D1 (DRD1), engrailed homolog 2 (EN2), met proto-oncogene (MET), methylenetetrahydrofolate reductase (MTHFR), solute carrier family 6 member 4 (SLC6A4), Synaptosomal-associated protein, 25kDa (SNAP-25) and vitamin D receptor (VDR). In the allele contrast model of cases versus healthy controls, significant associations were observed for Adrenoceptor Alpha 1B (ADRA1B), acetyl serotonin O - methyltransferase (ASMT), complement component 4B (C4B), dopamine receptor D3 (DRD3), met proto-oncogene (MET), neuroligin 4, X-linked (NLGN4), neurexin 1 (NRXN1), oxytocin receptor (OXTR), Serine/Threonine-Protein Kinase PFTAIRE-1 (PFTK1), Reelin (RELN) and Ras-like without CAAX 2 (RIT2). These significant findings provide further evidence for genetic factors' implication in ASDs offering new perspectives in means of prevention and prognosis.

Identification of Electrophysiological Changes in Alzheimer's Disease: A Microarray Based Transcriptomics and Molecular Pathway Analysis Study

Involvement of amyloid beta and tau proteins in pathogenesis of Alzheimer's disease (AD) has been studied extensively. However, electrophysiological activity, and cellular processes like membrane transport are mostly unstudied. Electrophysiological processes provide a bridge between brain activity and cognition, and show promise as translatable biomarkers in preclinical and clinical applications. Biochemical imbalance leads to change in glutamate-based neurotransmission, antioxidant capacity, and in membrane polarization-repolarization events, eventually, resulting in AD. We hypothesize that in AD, these processes are unified at a single metabolic hub and we carried out a holistic system-biology approach. In the present study, we integrated and analyzed multiple AD expression datasets from the GEO database to identify significant genes associated with electrophysiological pathways and attempted determination of interconnected canonical molecular pathways. Partek Genomic suite based expression analysis identified 200 significantly expressed genes using cut-off value of ≤ 0.05 and 2 fold change. Transducer of ERBB2, 2 (TOB2); lactotransferrin (LFT) and RAS-like, family 12 (RASL12) were most up-regulated genes, while neurofilament light polypeptide (NEFL); collagen, type V, alpha 2 (COL5A2); visinin-like 1 (VSNL1); cannabinoid receptor 1 (brain) (CNR1); neurofilament, medium polypeptide (NEFM); regulator of G-protein signaling 4 (RGS4), and synaptosomalassociated protein, 25kDa (SNAP25) were most down-regulated ones. Interestingly, we found majority of transporter genes identified in dataset as downregulated. Ingenuity pathways analysis revealed glutamate receptor signaling, CREB signaling, dopamine- DARPP32 feedback in cAMP signaling, fMLP signaling in neutrophils, and synaptic long term potentiation pathway playing critical role in AD pathophysiology and having correlation with electrophysiological dysfunction.

Polymorphism of the SNAP25 gene is associated with symptom improvement in schizophrenic patients treated with amisulpride.

Synaptosomal-associated protein 25kDa (SNAP25) is a promising candidate gene related to the treatment response to antipsychotics. Thus, the present study investigated the associations between polymorphisms of SNAP25 and the treatment response to amisulpride in patients with schizophrenia. This study enrolled 154 schizophrenic patients from six university hospitals in South Korea. All patients were assessed with the Positive and Negative Syndrome Scale (PANSS) and the Clinical Global Impression-Severity (CGI-S) scale at baseline and week 6 of treatment. Additionally, 101 subjects were genotyped for the rs8636 and rs3746544 single nucleotide polymorphisms (SNPs) of SNAP25. The genotype frequencies of rs8636 SNP significantly differed between responders and non-responders, measured by PANSS total score, in additive, recessive, and overdominant models. These findings suggest that SNAP25 might be a useful marker for predicting the response to antipsychotics. Future studies should include a larger number of subjects, a comprehensive array of SNAP25 SNPs, and functional analyses.

Zinc finger protein 804A (ZNF804A) and verbal deficits in individuals with autism.

In a genome-wide association study of autism, zinc finger protein 804A (ZNF804A) single nucleotide polymorphisms (SNPs) were found to be nominally associated in verbally deficient individuals with autism. Zinc finger protein 804A copy number variations (CNVs) have also been observed in individuals with autism. In addition, ZNF804A is known to be involved in theory of mind (ToM) tasks, and ToM deficits are deemed responsible for the communication and social challenges faced by individuals with autism. We hypothesized that ZNF804A could be a risk gene for autism. We examined the genetic association and CNVs of ZNF804A in 841 families in which 1 or more members had autism. We compared the expression of ZNF804A in the postmortem brains of individuals with autism (n = 8) and controls (n = 13). We also assessed in vitro the effect of ZNF804A silencing on the expression of several genes known to be involved in verbal efficiency and social cognition. We found that rs7603001 was nominally associated with autism (p = 0.018). The association was stronger (p = 0.008) in the families of individuals with autism who were verbally deficient (n = 761 families). We observed ZNF804A CNVs in 7 verbally deficient boys with autism. In ZNF804A knockdown cells, the expression of synaptosomal-associated protein, 25kDa (SNAP25) was reduced compared with controls (p = 0.009). The expression of ZNF804A (p = 0.009) and SNAP25 (p = 0.009) were reduced in the anterior cingulate gyrus (ACG) of individuals with autism. There was a strong positive correlation between the expression of ZNF804A and SNAP25 in the ACG (p < 0.001). Study limitations include our small sample size of postmortem brains. Our results suggest that ZNF804A could be a potential candidate gene mediating the intermediate phenotypes associated with verbal traits in individuals with autism.

Designing and analyzing the structure of Tat-BoNT/A(1-448) fusion protein: An in silico approach.

Clostridium botulinum type A (BoNT/A) produces a neurotoxin recently found to be useful as an injectable drug for the treatment of abnormal muscle contractions. The catalytic domain of this toxin which is responsible for the main toxin activity is a zinc metalloprotease that inhibits the release of neurotransmitter mediators in neuromuscular junctions. A cell penetrating cationic peptide, Tat, which is a truncated N-terminal part of the Tat protein from human immunodeficiency virus, can help the toxin penetrate the skin uninvasively. This study aimed at an in silico analyses of the Tat-BoNT/A(1-448) fusion protein structure. A genomic construct was designed and optimized based on E. coli codon usage. The structure of mRNA as well as the properties of hypothetical chimeric protein was then analyzed by bioinformatic tools. Afterwards, the secondary and tertiary structures of the fusion protein were predicted by GOR4 and I-TASSER online web servers. The interaction with synaptosomal associated protein 25kDa (SNAP-25) was also analyzed as a natural substrate for the toxin. Based on the studied secondary and tertiary structures of the protein, the selected order of fusion proteins provides the natural activity of each peptide. Energy calculating data show that the acquired thermodynamic ensemble related to the mRNA structure was-1473.2 kJ/mol (-352.10 kcal/mol) and both total protein energy (Etotal) and shape related energy(Eshape) were calculated as -2294.2kJ/mol (-548.32 kcal/mol). The stability index of TAT-BoNT/A was computed to be 27.22 which has an acceptable stability as compared to that of native BoNT/A (22.39).

Analysis of SNAP25 mRNA expression and promoter DNA methylation in brain areas of Alzheimer’s Disease patients

Alzheimer′s Disease (AD) is the most common cause of dementia in elderly people. The presynaptic terminal is an important site of pathological changes in AD, leading to synaptic loss in specific brain regions, such as in the cortex and hippocampus. In this study, we investigated synaptosomal-associated protein, 25-kDa (SNAP25) mRNA levels and promoter DNA methylation in post mortem brain tissues (entorhinal and auditory cortices and hippocampus) from healthy elderly and AD subjects as well as in peripheral blood leukocytes of young, healthy elderly and AD patients. mRNA quantification was performed by quantitative Reverse Transcription Polymerase Chain Reaction (qRT-PCR) using the ΔΔCT method and promoter DNA methylation was quantified by mass spectrometry using the Sequenom EpiTYPER platform. We observed a significant decrease in SNAP25 expression in AD across all the three brain regions in relation to the healthy elderly subjects, suggesting impairment in synaptic function. The changes in the auditory cortex reflected those observed in the hippocampus and entorhinal cortex, the primary areas affected in AD. However, no AD-associated differences in SNAP25 promoter DNA methylation were observed suggesting that other mechanisms may be involved in mediating the observed gene expression changes.

Decreased β‐cell insulin secretory function in aged rats due to impaired Ca2+ handling

Ageing is associated with an increased impairment in glucose homeostasis and an increased incidence of type2 diabetes. In this study, we evaluated β-cell function and its implications for glucose homeostasis in 24-month-old female Wistar rats. Aged rats showed lower plasma glucose levels in the fed and fasting states compared with control rats. In addition, insulinaemia in the fed state was reduced in the older rats. Insulin receptorβ (IRβ) expression was lower in the livers of the aged animals, whereas IRβ and Akt(1/2/3) protein expressions were higher in the muscles. These effects may contribute to the normal glucose tolerance observed in older rodents. Isolated islets from aged rats secreted less insulin in response to 8.3 and 16.7mm glucose. Accordingly, this group presented a lower [Ca(2+)](i) in the presence of glucose and a depolarizing stimulus (30mm K(+)). In addition, islets from aged rats showed reduced insulin secretion in response to 100μm carbachol (CCh), 10nm phorbol 12-myristate 13-acetate and 10μm forskolin. The expressions of protein kinaseC, protein kinaseA and exocytotic proteins, such as syntaxin1 and synaptosomal-associated protein 25kDa (SNAP-25), were similar in islets from aged and control rats. In conclusion, our evidence suggests that the increased incidence of type2 diabetes with age may be due to a progressive decline in β-cell secretory capacity due to disruption of Ca(2+) handling. Furthermore, the expression of proteins of the insulin transduction cascade showed an adaptive profile, with a compensatory increase in IRβ and Akt(1/2/3) in gastrocnemius muscles, which may maintain normal glucose homeostasis in 24-month-old rats.

Association study of schizophrenia and synaptosomal-associated protein 25kDa gene polymorphism

Objective To investigate the relationship between single nucleotide polymorphism(rs8636)in synaptosomal-associated protein 25kDa gene(SNAP-25)and schizophrenia.Methods The genotypes and alleles in 300 patients with schizophrenia and 300 normal controls were examined with polymerase chain reaction and restriction fragment length polymorphism technique.Analyzed the association between schizophrenia and polymorphism of SNAP-25 gene.Results ①There was no deviation from Hardy-Weinberg disequilibrium for the frequency distribution of genotypes and alleles in the two groups(X~2=2.69，v=1，P＞0.05；X~2=2.52，v=1，P＞0.05).②There were significant differences in the frequencies of the genotypes and alleles between patients andcontrols(X~2=6.454，P＜0.05；X~2=7.033，P＜0.05).③The frequency of C/C genotype(65.0%)and C alleles (79.7%)in patients were higher than that in the controls(X~2=5.848，P＜0.05；OR=1.50).The frequency of T/T genotype(5.7%)in patients was lower than that in the controls(X~2=2.453，P＞0.05).Conclusion There is a relationship between rs8636 in SNAP-25 gene and schizophrenia.The genotype C/C and alleles C may be a risk factor to the pathogenesis of schizophrenia. Key words: Schizophrenia; Synaptosomal-associated protein 25; Gene; Case-control study

Loss of synaptophysin and synaptosomal‐associated protein 25‐kDa (SNAP‐25) in elderly Down syndrome individuals

This study quantified the density of the synaptic proteins synaptophysin and synaptosomal-associated protein 25-kDa (SNAP-25) in brains from elderly Down's syndrome individuals. Six areas (frontal, occipital, parietal and temporal lobes, cerebellum and hippocampus) of post mortem brains from elderly Down's syndrome (DS) individuals (with reported functional memory problems and pathologically established Alzheimer's disease) and elderly controls were studied. Collectively in the six brain areas studied, there were significantly lower levels of both synaptophysin and SNAP-25 immunostaining in the DS group compared with controls. The elderly control group displayed a significant decrease in the densities of synaptophysin and SNAP-25 as a function of age at death (AAD; P < or = 0.001), whereas the DS group only showed a significant decrease as a function of AAD for synaptophysin. Assessing synaptic density as a function of Braak stage (BST) revealed a significant decrease in synaptophysin density for both groups. SNAP-25 was only significantly decreased as a function of BST in the DS group. Synaptic protein density was also shown to vary according to gender. Thus, both DS and control female subjects had a higher synaptic density of SNAP-25 than their male counterparts. In contrast, male DS and control individuals had a significantly greater density of synaptophysin than females. These results indicate that elderly DS individuals have lower synaptic densities of both analysed proteins than cognitively intact elderly individuals. Although AAD and BST show varying significance to decreases in protein density for both DS and control groups, results suggest that gender differences also play a role in the type of synaptic protein lost in elderly DS individuals.

P.1.a.018 Changes in the expression of NR1 subunit of NMDA receptor in schizophrenic hippocampus

Research efforts to identify and understand the pathophysiology of schizophrenia and bipolar illness are limited by the inability to study neuronal tissue of living patients. An alternative to sampling brain tissue from living patients is to measure neuronal proteins found in cerebral spinal fluid. One such candidate protein is synaptosomal-associated protein 25kDa. Our hypothesis is that the level of this protein in cerebral spinal fluid may be a marker of neuronal pathology. Cerebral spinal fluid from headache, schizophrenic, bipolar, and control subjects was used to measure the SNAP-25 level by quantitative dot blotting. Schizophrenic subjects had significantly elevated levels of SNAP-25 as compared to headache and control subjects. However, there was no significant difference between the bipolar group and schizophrenic or control groups. This study reports on a potentially useful clinical marker in schizophrenia, and the presence of elevated cerebral spinal fluid SNAP-25 may indicate alterations in neuronal functioning.

CSF SNAP-25 in Schizophrenia and Bipolar Illness: A Pilot Study

Research efforts to identify and understand the pathophysiology of schizophrenia and bipolar illness are limited by the inability to study neuronal tissue of living patients. An alternative to sampling brain tissue from living patients is to measure neuronal proteins found in cerebral spinal fluid. One such candidate protein is synaptosomal-associated protein 25kDa. Our hypothesis is that the level of this protein in cerebral spinal fluid may be a marker of neuronal pathology. Cerebral spinal fluid from headache, schizophrenic, bipolar, and control subjects was used to measure the SNAP-25 level by quantitative dot blotting. Schizophrenic subjects had significantly elevated levels of SNAP-25 as compared to headache and control subjects. However, there was no significant difference between the bipolar group and schizophrenic or control groups. This study reports on a potentially useful clinical marker in schizophrenia, and the presence of elevated cerebral spinal fluid SNAP-25 may indicate alterations in neuronal functioning.