IntroductionThe molecular underpinnings of the dissociation of cognitive performance and neuropathological burden are poorly understood, and there are currently no known genetic or epigenetic determinants of the dissociation.Methods and findings“Residual cognition” was quantified by regressing out the effects of cerebral pathologies and demographic characteristics on global cognitive performance proximate to death. To identify genes influencing residual cognition, we leveraged neuropathological, genetic, epigenetic, and transcriptional data available for deceased participants of the Religious Orders Study (n = 492) and the Rush Memory and Aging Project (n = 487). Given that our sample size was underpowered to detect genome-wide significance, we applied a multistep approach to identify genes influencing residual cognition, based on our prior observation that independent genetic and epigenetic risk factors can converge on the same locus. In the first step (n = 979), we performed a genome-wide association study with a predefined suggestive p < 10−5, and nine independent loci met this threshold in eight distinct chromosomal regions. Three of the six genes within 100 kb of the lead SNP are expressed in the dorsolateral prefrontal cortex (DLPFC): UNC5C, ENC1, and TMEM106B. In the second step, in the subset of participants with DLPFC DNA methylation data (n = 648), we found that residual cognition was related to differential DNA methylation of UNC5C and ENC1 (false discovery rate < 0.05). In the third step, in the subset of participants with DLPFC RNA sequencing data (n = 469), brain transcription levels of UNC5C and ENC1 were evaluated for their association with residual cognition: RNA levels of both UNC5C (estimated effect = −0.40, 95% CI −0.69 to −0.10, p = 0.0089) and ENC1 (estimated effect = 0.0064, 95% CI 0.0033 to 0.0096, p = 5.7 × 10−5) were associated with residual cognition. In secondary analyses, we explored the mechanism of these associations and found that ENC1 may be related to the previously documented effect of depression on cognitive decline, while UNC5C may alter the composition of presynaptic terminals. Of note, the TMEM106B allele identified in the first step as being associated with better residual cognition is in strong linkage disequilibrium with rs1990622A (r2 = 0.66), a previously identified protective allele for TDP-43 proteinopathy. Limitations include the small sample size for the genetic analysis, which was underpowered to detect genome-wide significance, the evaluation being limited to a single cortical region for epigenetic and transcriptomic data, and the use of categorical measures for certain non-amyloid-plaque, non-neurofibrillary-tangle neuropathologies.ConclusionsThrough a multistep analysis of cognitive, neuropathological, genomic, epigenomic, and transcriptomic data, we identified ENC1 and UNC5C as genes with convergent genetic, epigenetic, and transcriptomic evidence supporting a potential role in the dissociation of cognition and neuropathology in an aging population, and we expa...

Background Synaptic dysfunction in schizophrenia may be associated with abnormal expression or function of SNARE proteins (syntaxin, SNAP25, VAMP), forming the molecular complex underlying neurosecretion. The impact of such abnormalities on efficient SNARE heterotrimer formation is poorly understood. We investigated putative SNARE dysfunction, along with possible roles for the SNARE binding partners Munc18-1, complexins (Cplx) 1/2 and synaptotagmin, in brains from autopsies of individuals with and without schizophrenia. Methods Postmortem samples were obtained from orbitofrontal (OFC) and/or anterior cingulate (ACC) cortices from two separate cohorts (n = 15+15 schizophrenia cases, n = 13+15 controls). SNARE interactions were studied by immunoprecipitation and one- or two-dimensional blue native electrophoresis (BN-PAGE). Results In the first cohort, syntaxin, Munc18-1 and Cplx1, but not VAMP, Cplx2 or synaptotagmin, were two-fold enriched in SNAP25-immunoprecipitated products from schizophrenia OFC in the absence of any alterations in total tissue homogenate levels of these proteins. In BN-PAGE, the SNARE heterotrimer was identified as a 150-kDa complex, increased in schizophrenia samples from Cohort 1 (OFC: +45%; ACC: +44%) and Cohort 2 (OFC: +40%), with lower 70-kDa SNAP25-VAMP dimer (−37%) in the OFC. Upregulated 200-kDa SNARE-Cplx1 (+65%), and downregulated 550-kDa Cplx1-containing oligomers (−24%) in schizophrenia OFC were identified by BN-PAGE. These findings were not explained by postmortem interval, antipsychotic medication, or other potentially confounding variables. Conclusions The findings support the hypothesis of upregulated SNARE complex formation in schizophrenia OFC, possibly favored by enhanced affinity for Munc18-1 and/or Cplx1. These alterations offer new therapeutic targets for schizophrenia.

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.

Chronic prescription of antipsychotics seems to lose its therapeutic benefits in the prevention of recurring psychotic symptoms. In many instances, the occurrence of relapse from initial remission is followed by an increase in dose of the prescribed antipsychotic. The current understanding of why this occurs is still in its infancy, but a controversial idea that has regained attention recently is the notion of iatrogenic dopamine supersensitivity. Studies on cell cultures and animal models have shown that long-term antipsychotic use is linked to both an upregulation of dopamine D2-receptors in the striatum and the emergence of enhanced receptor affinity to endogenous dopamine. These findings have been hypothesized to contribute to the phenomenon known as dopamine supersensitivity psychosis (DSP), which has been clinically typified as the foundation of rebound psychosis, drug tolerance, and tardive dyskinesia. The focus of this review is the update of evidence behind the classification of antipsychotic induced DSP and an investigation of its relationship to treatment resistance. Since antipsychotics are the foundation of illness management, a greater understanding of DSP and its prevention may greatly affect patient outcomes.

Progressive accumulation of Alzheimer's disease-related pathology is associated with cognitive dysfunction. Differences in cognitive reserve may contribute to individual differences in cognitive function in the presence of comparable neuropathology. The protective effects of cognitive reserve could contribute differentially in early versus late stages of the disease. We investigated presynaptic proteins as measures of brain reserve (a subset of total cognitive reserve), and used Braak staging to estimate the progression of Alzheimer's disease. Antemortem evaluations of cognitive function, postmortem assessments of pathologic indices, and presynaptic protein analyses, including the complexins I and II as respective measures of inhibitory and excitatory terminal function, were assayed in multiple key brain regions in 418 deceased participants from a community study. After covarying for demographic variables, pathologic indices, and overall synapse density, lower brain complexin-I and -II levels contributed to cognitive dysfunction (P < 0.01). Each complexin appeared to be dysregulated at a different Braak stage. Inhibitory complexin-I explained 14.4% of the variance in global cognition in Braak 0-II, while excitatory complexin-II explained 7.3% of the variance in Braak V-VI. Unlike other presynaptic proteins, complexins did not colocalize with pathologic tau within neuritic plaques, suggesting that these functional components of the synaptic machinery are cleared early from dystrophic neurites. Moreover, complexin levels showed distinct patterns of change related to memory challenges in a rat model, supporting the functional specificity of these proteins. The present results suggest that disruption of inhibitory synaptic terminals may trigger early cognitive impairment, while excitatory terminal disruption may contribute relatively more to later cognitive impairment.

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BackgroundPresynaptic terminals contribute to cognitive reserve, balancing the effects of age-related pathologies on cognitive function in the elderly. The presynaptic protein Munc18-1, alternatively spliced into long (M18L) or short (M18S) isoforms, is a critical modulator of neurotransmission. While subtle alterations in Munc18-1 have been shown to cause severe neuropsychiatric disorders with cognitive impairment, little information is known regarding the specific roles of Munc18-1 splice variants. We first investigated functional and anatomical features evidencing the divergent roles of M18L and M18S, and then evaluated their contribution to the full range of age-related cognitive impairment in the dorsolateral prefrontal cortex of a large sample of participants from a community-based aging study, including subjects with no-(NCI, n = 90), or mild-(MCI, n = 86) cognitive impairment, or with clinical dementia (n = 132). Finally, we used APP23 mutant mice to study the association between M18L/S and the time-dependent accumulation of common Alzheimer’s disease pathology.ResultsUsing isoform-specific antibodies, M18L was localized to the synaptosomal fraction, with a distribution matching lipid raft microdomains. M18S was found widely across cytosolic and synaptosomal compartments. Immunocytochemical studies identified M18L in perisomatic, GABAergic terminals, while M18S was broadly distributed in GABAergic and glutamatergic terminals. Using regression models taking into account multiple age-related pathologies, age, education and sex, global cognitive function was associated with the level of M18L (p = 0.006) but not M18S (p = 0.88). Mean M18L in dementia cases was 51 % lower than in NCI cases (p < 0.001), and each unit of M18L was associated with a lower likelihood of dementia (odds ratio = 0.68, 95 % confidence interval = 0.50–0.90, p = 0.008). In contrast, M18S balanced across clinical and pathologically diagnosed groups. M18L loss may not be caused by age-related amyloid pathology, since APP23 mice (12- and 22-months of age) had unchanged cortical levels of M18L/S compared with wild-type animals.ConclusionsM18L was localized to presynaptic inhibitory terminals, and was associated with cognitive function and protection from dementia in an elderly, community-based cohort. Lower M18L in inhibitory presynaptic terminals may be an early, independent contributor to cognitive decline.Electronic supplementary materialThe online version of this article (doi:10.1186/s13024-015-0061-4) contains supplementary material, which is available to authorized users.

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