Synapses are essential components of neurons and allow information to travel coordinately throughout the nervous system to adjust behavior to environmental stimuli and to control body functions, memories, and emotions. Thus, optimal synaptic communication is required for proper brain physiology, and slight perturbations of synapse function can lead to brain disorders. In fact, increasing evidence has demonstrated the relevance of synapse dysfunction as a major determinant of many neurological diseases. This notion has led to the concept of synaptopathies as brain diseases with synapse defects as shared pathogenic features. In this review, which was initiated at the 13th International Society for Neurochemistry Advanced School, we discuss basic concepts of synapse structure and function, and provide a critical view of how aberrant synapse physiology may contribute to neurodevelopmental disorders (autism, Down syndrome, startle disease, and epilepsy) as well as neurodegenerative disorders (Alzheimer and Parkinson disease). We finally discuss the appropriateness and potential implications of gathering synapse diseases under a single term. Understanding common causes and intrinsic differences in diseaseassociated synaptic dysfunction could offer novel clues toward synapse-based therapeutic intervention for neurological and neuropsychiatric disorders.
Neuronal networks are balanced by mechanisms of homeostatic plasticity, which adjusts synaptic strength via molecular and morphological changes in the pre- and post-synapse. Here, we wondered whether the hyaluronic acid-based extracellular matrix (ECM) of the brain is involved in mechanisms of homeostatic plasticity. We hypothesized that the ECM, being rich in chondroitin sulfate proteoglycans such as brevican, which are suggested to stabilize synapses by their inhibitory effect on structural plasticity, must be remodelled to allow for structural and molecular changes during conditions of homeostatic plasticity. We found a high abundance of cleaved brevican fragments throughout the hippocampus and cortex and in neuronal cultures, with the strongest labelling in perineuronal nets on parvalbumin-positive interneurons. Using an antibody specific for a brevican fragment cleaved by the matrix metalloprotease ADAMTS4, we identified the enzyme as the main brevican-processing protease. Interestingly, we found ADAMTS4 largely associated with synapses. After inducing homeostatic plasticity in neuronal cell cultures by prolonged network inactivation, we found increased brevican processing at inhibitory as well as excitatory synapses, which is in line with the ADAMTS4 subcellular localization. Thus, the ECM is remodelled in conditions of homeostatic plasticity, which may liberate synapses to allow for a higher degree of structural plasticity.
Cortical areas of the juvenile rodent brain display a high degree of structural and functional plasticity, which disappears later in development. Coincident with the decline of plasticity 1) the hyaluronic acid-based extracellular matrix (ECM) of the brain, which stabilizes synapses and neuronal circuit is formed and 2) N-methyl-D-aspartate subtype of ionotropic glutamate receptors (NMDARs) implied in synaptic plasticity switch from mainly GluN2B to GluN2A subunit-containing receptors. Here we tested the hypothesis that ECM influences the NMDAR subunit composition in dissociated neuronal cultures. Experimental removal of ECM using hyaluronidase induced an increase in surface expression of GluN2B. This was due to decreased endocytosis of surface GluNB-containing receptors. We further found a reduction in phosphorylation at Tyr1472, which negatively regulates their binding to the endocytotic AP2 complex. We propose that maturation of ECM could induce switch in NMDAR composition necessary for normal adult synaptic plasticity and that increased expression of GluN2B contributes to rejuvenation of plasticity after ECM removal in vivo.
Many journals, including the Journal of Neurochemistry, enable authors to list peer reviewers as 'preferred' or 'opposed' suggestions to the editor. At the Journal of Neurochemistry, the handling editor (HE) may follow recommendations or select non-author-suggested reviewers (non-ASRs). We investigated whether selection of author-suggested reviewers (ASRs) influenced decisions on a paper, and whether differences might be related to a reviewer's, editor's or manuscript's geographical location. In this retrospective analysis, we compared original research articles submitted to the Journal of Neurochemistry from 2013 through 2016 that were either reviewed exclusively by non-ASRs, by at least one ASR, by at least one reviewer marked by the author as 'opposed' or none. Manuscript outcome, reviewer rating of manuscript quality, rating of the reviewers' performance by the editor (R-score), time to review, and the country of the editor, reviewers and manuscript author were analyzed using non-parametric rank-based comparisons, chi-square (χ ) analysis, multivariate linear regression, one-way analysis of variance, and inter-rater reliability determination. Original research articles that had been reviewed by at least one ASR stood a higher chance of being accepted (525/1006 = 52%) than papers that had been reviewed by non-ASRs only (579/1800 = 32%). An article was 2.4 times more likely to be accepted than rejected by an ASR compared to a non-ASR (Pearson's χ (1) = 181.3, p < 0.05). At decision, the editor did not simply follow the reviewers' recommendation but had a balancing role: Rates of recommendation from reviewers for rejection were 11.2% (139/1241) with ASRs versus 29.0% (1379/4755) with non-ASRs (this is a ratio of 0.39 where 1 means no difference between rejection rates for both groups), whereas the proportion of final decisions to reject was 24.7% (248/1006) versus 45.7% (822/1800) (a ratio of 0.54, considerably closer to 1). Recommendations by non-ASRs were more favorable for manuscripts from USA/Canada and Europe than for Asia/Pacific or Other countries. ASRs judged North American manuscripts most favorably, and judged papers generally more positively (mean: 2.54 on a 1-5 scale) than did non-ASRs (mean: 3.16) reviewers, whereas time for review (13.28 vs. 13.20 days) did not differ significantly between these groups. We also found that editors preferably assigned reviewers from their own geographical region, but there was no tendency for reviewers to judge papers from their own region more favorably. Our findings strongly confirm a bias toward lower rejection rates when ASRs assess a paper, which led to the decision to abandon the option to recommend reviewers at the Journal of Neurochemistry. Open Data: Materials are available on https://osf.io/jshg7/.
The Open Science Framework (OSF) has the mission to increase openness, integrity, and reproducibility in research. The Journal of Neurochemistry became a signatory of their Transparency and Openness guidelines in 2016, which provides eight modular standards (Citation standards, Data Transparency, Analytic Methods/Code Transparency, Research Materials Transparency, Design and Analysis Transparency, Study Pre-registration, Analysis Plan Transparency, Replication) with increasing levels of stringency. Furthermore, OSF recommends and offers a collection of practices intended to make scientific processes and results more transparent and available in a standardized way for reuse to people outside the research team. It includes making research materials, data, and laboratory procedures freely accessible online to anyone. This editorial announces the decision of the Journal of Neurochemistry to introduce Open Science Badges, maintained by the Open Science Badges Committee and by the Center for Open Science (COS). The Open Science Badges, visual icons placed on publications, certify that an open practice was followed and signal to readers that an author has shared the corresponding research evidence, thus, allowing an independent researcher to understand how to reproduce the procedure.
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