Endosomal sorting protein SNX4 limits synaptic vesicle docking and release.

Sorting nexin 4 (SNX4) is an evolutionary conserved organizer of membrane recycling. In neurons, SNX4 accumulates in synapses, but how SNX4 affects synapse function remains unknown. We generated a conditional SNX4 knock-out mouse model and report that SNX4 cKO synapses show enhanced neurotransmission during train stimulation, while the first evoked EPSC was normal.

A de novo missense mutation in synaptotagmin-1 associated with neurodevelopmental disorder desynchronizes neurotransmitter release.

Synaptotagmin-1 (Syt1) is a presynaptic calcium sensor with two calcium binding domains, C2A and C2B, that triggers action potential-induced synchronous neurotransmitter release, while suppressing asynchronous and spontaneous release. We identified a de novo missense mutation (P401L) in the C2B domain in a patient with developmental delay and autistic symptoms. Expressing the orthologous mouse mutant (P400L) in cultured Syt1 null mutant neurons revealed a reduction in dendrite outgrowth with a proportional reduction in synapses.

Following Excitation/Inhibition Ratio Homeostasis from Synapse to EEG in Monogenetic Neurodevelopmental Disorders.

Pharmacological options for neurodevelopmental disorders are limited to symptom suppressing agents that do not target underlying pathophysiological mechanisms. Studies on specific genetic disorders causing neurodevelopmental disorders have elucidated pathophysiological mechanisms to develop more rational treatments. Here, we present our concerted multi-level strategy 'BRAINMODEL', focusing on excitation/inhibition ratio homeostasis across different levels of neuroscientific interrogation.

Post-tetanic potentiation lowers the energy barrier for synaptic vesicle fusion independently of Synaptotagmin-1.

Previously, we showed that modulation of the energy barrier for synaptic vesicle fusion boosts release rates supralinearly (Schotten, 2015). Here we show that mouse hippocampal synapses employ this principle to trigger Ca-dependent vesicle release and post-tetanic potentiation (PTP). We assess energy barrier changes by fitting release kinetics in response to hypertonic sucrose.

User-Centred Approach to Design an Online Social Support Platform for Seniors : Identification of Users' Types and Their Requirements.

A well-designed social platform has the potential to reduce senior isolation and promote active ageing. However, to design tools that respond to the user need it is important to understand what types of seniors will use it and what are their needs. Through a user-oriented approach at several design stage: focus group, co-creation and usability test we were able to identify the different roles related to the use of the platform, which allowed us to classify them by type, each type having very specific needs.

Doc2 Proteins Are Not Required for the Increased Spontaneous Release Rate in Synaptotagmin-1-Deficient Neurons.

Regulated secretion is controlled by Ca sensors with different affinities and subcellular distributions. Inactivation of (synaptotagmin-1), the main Ca sensor for synchronous neurotransmission in many neurons, enhances asynchronous and spontaneous release rates, suggesting that Syt1 inhibits other sensors with higher Ca affinities and/or lower cooperativities. Such sensors could include Doc2a and Doc2b, which have been implicated in spontaneous and asynchronous neurotransmitter release and compete with Syt1 for binding SNARE complexes.

Publisher Correction: Synaptotagmin-1 enables frequency coding by suppressing asynchronous release in a temperature dependent manner.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Axial pelvis range of motion affects thorax-pelvis timing during gait.

During gait, patients with pelvic girdle pain and low back pain demonstrate an altered phase relationship between axial thorax and pelvis rotations (thorax-pelvis relative phase). This could be the result of an increase in axial pelvis range of motion (ROM) which has been observed in these patients as well. To establish this relationship, we investigated if altered axial pelvis ROM during gait affects thorax-pelvis relative phase in 12 healthy subjects.

Synaptotagmin-1 enables frequency coding by suppressing asynchronous release in a temperature dependent manner.

To support frequency-coded information transfer, mammalian synapses tightly synchronize neurotransmitter release to action potentials (APs). However, release desynchronizes during AP trains, especially at room temperature. Here we show that suppression of asynchronous release by Synaptotagmin-1 (Syt1), but not release triggering, is highly temperature sensitive, and enhances synchronous release during high-frequency stimulation.

SynGO: An Evidence-Based, Expert-Curated Knowledge Base for the Synapse.

Synapses are fundamental information-processing units of the brain, and synaptic dysregulation is central to many brain disorders ("synaptopathies"). However, systematic annotation of synaptic genes and ontology of synaptic processes are currently lacking. We established SynGO, an interactive knowledge base that accumulates available research about synapse biology using Gene Ontology (GO) annotations to novel ontology terms: 87 synaptic locations and 179 synaptic processes.

Active Involvement of People with Dementia: A Systematic Review of Studies Developing Supportive Technologies.

Although there are promising benefits of supportive technology in dementia care, use of these technologies is still limited. It is challenging for researchers and developers in this field to actively involve people with dementia in development. This review updates and builds on existing knowledge by including a contemporary and relevant perspective.

A Single-Cell Model for Synaptic Transmission and Plasticity in Human iPSC-Derived Neurons.

Synaptic dysfunction is associated with many brain disorders, but robust human cell models to study synaptic transmission and plasticity are lacking. Instead, current in vitro studies on human neurons typically rely on spontaneous synaptic events as a proxy for synapse function. Here, we describe a standardized in vitro approach using human neurons cultured individually on glia microdot arrays that allow single-cell analysis of synapse formation and function.

Designing an Online Social Support Platform Through Co-Creation with Seniors.

The high number of seniors that feels excluded of society highlights the necessity to promote active ageing. This intention can be supported through online platforms that encourage participation in social activities. The goal of the present study was to identify design principles of online support platforms for seniors through focus groups and to ideate the platform through co-creation sessions.

MIR137 schizophrenia-associated locus controls synaptic function by regulating synaptogenesis, synapse maturation and synaptic transmission.

The MIR137 locus is a replicated genetic risk factor for schizophrenia. The risk-associated allele is reported to increase miR-137 expression and miR-137 overexpression alters synaptic transmission in mouse hippocampus. We investigated the cellular mechanisms underlying these observed effects in mouse hippocampal neurons in culture.

Protein instability, haploinsufficiency, and cortical hyper-excitability underlie STXBP1 encephalopathy.

De novo heterozygous mutations in STXBP1/Munc18-1 cause early infantile epileptic encephalopathies (EIEE4, OMIM #612164) characterized by infantile epilepsy, developmental delay, intellectual disability, and can include autistic features. We characterized the cellular deficits for an allelic series of seven STXBP1 mutations and developed four mouse models that recapitulate the abnormal EEG activity and cognitive aspects of human STXBP1-encephalopathy. Disease-causing STXBP1 variants supported synaptic transmission to a variable extent on a null background, but had no effect when overexpressed on a heterozygous background.

Munc13-1 and Munc18-1 together prevent NSF-dependent de-priming of synaptic vesicles.

Synaptic transmission requires a stable pool of release-ready (primed) vesicles. Here we show that two molecules involved in SNARE-complex assembly, Munc13-1 and Munc18-1, together stabilize release-ready vesicles by preventing de-priming. Replacing neuronal Munc18-1 by a non-neuronal isoform Munc18-2 (Munc18-1/2SWAP) supports activity-dependent priming, but primed vesicles fall back into a non-releasable state (de-prime) within seconds.

Phosphorylation of synaptotagmin-1 controls a post-priming step in PKC-dependent presynaptic plasticity.

Presynaptic activation of the diacylglycerol (DAG)/protein kinase C (PKC) pathway is a central event in short-term synaptic plasticity. Two substrates, Munc13-1 and Munc18-1, are essential for DAG-induced potentiation of vesicle priming, but the role of most presynaptic PKC substrates is not understood. Here, we show that a mutation in synaptotagmin-1 (Syt1(T112A)), which prevents its PKC-dependent phosphorylation, abolishes DAG-induced potentiation of synaptic transmission in hippocampal neurons.

Functional characterization of the PCLO p.Ser4814Ala variant associated with major depressive disorder reveals cellular but not behavioral differences.

Genome-wide association studies have suggested a role for a genetic variation in the presynaptic gene PCLO in major depressive disorder (MDD). As with many complex traits, the PCLO variant has a small contribution to the overall heritability and the association does not always replicate. One variant (rs2522833, p.

Additive effects on the energy barrier for synaptic vesicle fusion cause supralinear effects on the vesicle fusion rate.

The energy required to fuse synaptic vesicles with the plasma membrane ('activation energy') is considered a major determinant in synaptic efficacy. From reaction rate theory, we predict that a class of modulations exists, which utilize linear modulation of the energy barrier for fusion to achieve supralinear effects on the fusion rate. To test this prediction experimentally, we developed a method to assess the number of releasable vesicles, rate constants for vesicle priming, unpriming, and fusion, and the activation energy for fusion by fitting a vesicle state model to synaptic responses induced by hypertonic solutions.

Empirical Bayesian random censoring threshold model improves detection of differentially abundant proteins.

A challenge in proteomics is that many observations are missing with the probability of missingness increasing as abundance decreases. Adjusting for this informative missingness is required to assess accurately which proteins are differentially abundant. We propose an empirical Bayesian random censoring threshold (EBRCT) model that takes the pattern of missingness in account in the identification of differential abundance.

Molecular machines in the synapse: overlapping protein sets control distinct steps in neurosecretion.

Activity regulated neurotransmission shapes the computational properties of a neuron and involves the concerted action of many proteins. Classical, intuitive working models often assign specific proteins to specific steps in such complex cellular processes, whereas modern systems theories emphasize more integrated functions of proteins. To test how often synaptic proteins participate in multiple steps in neurotransmission we present a novel probabilistic method to analyze complex functional data from genetic perturbation studies on neuronal secretion.

Functional gene group analysis identifies synaptic gene groups as risk factor for schizophrenia.

Schizophrenia is a highly heritable disorder with a polygenic pattern of inheritance and a population prevalence of ~1%. Previous studies have implicated synaptic dysfunction in schizophrenia. We tested the accumulated association of genetic variants in expert-curated synaptic gene groups with schizophrenia in 4673 cases and 4965 healthy controls, using functional gene group analysis.

Automated analysis of neuronal morphology, synapse number and synaptic recruitment.

The shape, structure and connectivity of nerve cells are important aspects of neuronal function. Genetic and epigenetic factors that alter neuronal morphology or synaptic localization of pre- and post-synaptic proteins contribute significantly to neuronal output and may underlie clinical states. To assess the impact of individual genes and disease-causing mutations on neuronal morphology, reliable methods are needed.