A5070426008- Cellular transport and secretion
- Neuroscience and Neuropharmacology Research
- Lipid Membrane Structure and Behavior
- Photoreceptor and optogenetics research
- Receptor Mechanisms and Signaling
- Ion channel regulation and function
- Pancreatic function and diabetes
- Retinal Development and Disorders
- Neuroscience and Neural Engineering
- Single-cell and spatial transcriptomics
- Neural dynamics and brain function
- Genetics and Neurodevelopmental Disorders
- Neurotransmitter Receptor Influence on Behavior
- Bioinformatics and Genomic Networks
- Biomedical Text Mining and Ontologies
- Neurobiology and Insect Physiology Research
- Machine Learning in Bioinformatics
- Advanced Fluorescence Microscopy Techniques
- Cardiac electrophysiology and arrhythmias
- Cell Image Analysis Techniques
- Functional Brain Connectivity Studies
- Orbital Angular Momentum in Optics
- Genetic Associations and Epidemiology
- Photochromic and Fluorescence Chemistry
- Quantum Electrodynamics and Casimir Effect
Amsterdam Neuroscience
2010-2025
Amsterdam UMC Location Vrije Universiteit Amsterdam
2015-2024
Amsterdam University Medical Centers
2020-2024
Cognitive Research (United States)
2015-2024
Vrije Universiteit Amsterdam
2006-2020
Radboud University Nijmegen
2001-2004
Leiden University
1997
“Spontaneous” Release Trigger Synaptic vesicle release occurs in different phases that can be tightly coupled to action potentials (synchronous), immediately following (asynchronous), or as stochastic events not triggered by (spontaneous). The protein synaptotagmin is thought act the Ca 2+ sensor synchronous phase, but for other two phases, sensors have been identified. Groffen et al. (p. 1614 , published online 11 February) now show cytoplasmic proteins known Doc2 (double C2 domain) are...
The shape, structure and connectivity of nerve cells are important aspects neuronal function. Genetic epigenetic factors that alter morphology or synaptic localization pre- post-synaptic proteins contribute significantly to output may underlie clinical states. To assess the impact individual genes disease-causing mutations on morphology, reliable methods needed. Unfortunately, manual analysis immuno-fluorescence images neurons quantify shape synapse number, size distribution is...
Prompt recovery after intense activity is an essential feature of most mammalian synapses. Here we show that synapses with reduced expression the presynaptic gene munc18-1 suffer from increased depression during stimulation at glutamatergic, GABAergic, and neuromuscular Conversely, overexpression makes these recover faster. Concomitant changes in readily releasable vesicle pool its refill kinetics were found. The number vesicles docked active zone total per terminal correlated both levels...
Schizophrenia is a highly heritable disorder with polygenic pattern of inheritance and population prevalence ∼1%. Previous studies have implicated synaptic dysfunction in schizophrenia. We tested the accumulated association genetic variants expert-curated gene groups schizophrenia 4673 cases 4965 healthy controls, using functional group analysis. Identifying genes similar cellular function rather than isolation may clinical implications for finding additional drug targets. found that 1026...
De novo heterozygous mutations in STXBP1/Munc18-1 cause early infantile epileptic encephalopathies (EIEE4, OMIM #612164) characterized by epilepsy, developmental delay, intellectual disability, and can include autistic features. We the cellular deficits for an allelic series of seven STXBP1 developed four mouse models that recapitulate abnormal EEG activity cognitive aspects human STXBP1-encephalopathy. Disease-causing variants supported synaptic transmission to a variable extent on null...
The energy required to fuse synaptic vesicles with the plasma membrane (‘activation energy’) is considered a major determinant in efficacy. From reaction rate theory, we predict that class of modulations exists, which utilize linear modulation barrier for fusion achieve supralinear effects on rate. To test this prediction experimentally, developed method assess number releasable vesicles, constants vesicle priming, unpriming, and fusion, activation by fitting state model responses induced...
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 neurons typically rely spontaneous events as a proxy for synapse function. Here, we describe standardized approach using cultured individually glia microdot arrays that allow single-cell analysis of formation We show single glutamatergic or GABAergic forebrain differentiated from induced pluripotent stem...
Abstract 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 vesicles by preventing de-priming. Replacing neuronal Munc18-1 non-neuronal isoform Munc18-2 (Munc18-1/2SWAP) supports activity-dependent priming, but primed fall back into non-releasable state (de-prime) within seconds. deficiency produces similar defect. Inhibitors N -ethylmaleimide sensitive...
Secretory vesicles dock at the plasma membrane before they undergo fusion. Molecular docking mechanisms are poorly defined but believed to be independent of SNARE proteins. Here, we challenged this hypothesis by acute deletion target SNARE, syntaxin, in vertebrate neurons and neuroendocrine cells. Deletion resulted fusion arrest both systems. No defects were observed synapses, line with previous observations. However, a drastic reduction morphologically docked secretory was chromaffin...
Although cognitive ability is a highly heritable complex trait, only few genes have been identified, explaining relatively low proportions of the observed trait variation.This implies that hundreds small effect may be importance for ability.We applied an innovative method in which we tested groups defined according to cellular function (functional gene group analysis).Using initial sample 627 subjects, this functional analysis detected synaptic heterotrimeric guanine nucleotide binding...
The MIR137 locus is a replicated genetic risk factor for schizophrenia. risk-associated allele reported to increase miR-137 expression and overexpression alters synaptic transmission in mouse hippocampus. We investigated the cellular mechanisms underlying these observed effects hippocampal neurons culture. First, we correlated of genes human postmortem brain. Some evidence increased MIR137HG was observed, especially hippocampus disease-associated genotype. Second, neurons, confirmed...
Significance Synapses can be temporarily strengthened by bursts of action potentials, which are thought to a central aspect information processing in the brain. This study provides evidence that protein kinase C (PKC)-dependent phosphorylation synaptotagmin-1 is an essential step this strengthening. A mutation prevents abolishes strengthening, both after potential and upon direct PKC activation synthetic analog diacylglycerol, whereas basal synaptic transmission unaffected. suggests acts...
Autoinhibitory serotonin 1A receptors (5-HT ) in dorsal raphé nucleus (DRN) have been implicated chronic depression and actions of selective reuptake inhibitors (SSRI). Due to experimental limitations, it was never studied at single-cell level whether changes 5-HT receptor functionality occur during SSRI treatment. Here we address this question a social stress paradigm rats that mimics anhedonia, core symptom depression. We used whole cell patch-clamp recordings 5-HT- baclophen-induced...
Abstract A comprehensive, computable representation of the functional repertoire all macromolecules encoded within human genome is a foundational resource for biology and biomedical research. The Gene Ontology Consortium has been working towards this goal by generating structured body information about gene functions, which now includes experimental findings reported in more than 175,000 publications genes experimentally tractable model organisms 1,2 . Here, we describe results large,...
Rapid calcium concentration changes in postsynaptic structures are crucial for synaptic plasticity. Thus far, the determinants of dynamics have been studied predominantly based on decay kinetics transients. Calcium rise times spines response to single action potentials (AP) almost never measured due technical limitations, but they could be With high-speed, precisely-targeted, two-photon point imaging we both and secondary dendrites neocortical pyramidal neurons. We found that...
Synaptotagmin-1 (Syt1) is a presynaptic calcium sensor with two binding domains, C2A and C2B, that triggers action potential-induced synchronous neurotransmitter release, while suppressing asynchronous spontaneous release. We identified de novo missense mutation (P401L) in the C2B domain patient developmental delay autistic symptoms. Expressing orthologous mouse mutant (P400L) cultured Syt1 null neurons revealed reduction dendrite outgrowth proportional synapses. This was not observed single
Activity and calcium‐dependent release of neurotransmitters from the somatodendritic compartment is an important signalling mechanism between neurones throughout brain. NMDA receptors vesicles filled with occur in close proximity many brain areas. It unknown whether calcium influx through these can trigger directly, or postsynaptic action potential firing necessary for vesicles. Here we addressed this question by studying local serotonin (5‐HT) dorsal raphé nucleus (DRN) neurones. We...
A challenge in proteomics is that many observations are missing with the probability of missingness increasing as abundance decreases. Adjusting for this informative required to assess accurately which proteins differentially abundant. We propose an empirical Bayesian random censoring threshold (EBRCT) model takes pattern account identification differential abundance. compare our four alternatives, one considers values completely at (MCAR model), a fixed each protein species (fixed model)...
A minimal model is presented to explain changes in frequency, shape, and amplitude of Ca2+ oscillations the neuroendocrine melanotrope cell Xenopus Laevis. It describes as a plasma membrane oscillator with influx extracellular via voltage-gated channels membrane. The show specific features that cannot be explained by previous models for electrically bursting cells using one set parameters. assumes KCa-channel slow Ca2+-dependent gating kinetics initiates terminates bursts. this channel cause...
Abstract To support frequency-coded information transfer, mammalian synapses tightly synchronize neurotransmitter release to action potentials (APs). However, desynchronizes during AP trains, especially at room temperature. Here we show that suppression of asynchronous by Synaptotagmin-1 (Syt1), but not triggering, is highly temperature sensitive, and enhances synchronous high-frequency stimulation. In Syt1-deficient synapses, increased with temperature, opposite wildtype synapses. Mutations...
Abstract Ionic membrane conductances of normal rat kidney (NRK) fibroblasts were characterized by whole‐cell voltage‐clamp experiments on single cells and small cell clusters their role in action potential firing these monolayers was studied current‐clamp experiments. Activation an L‐type calcium conductance (G CaL ) is responsible for the initiation potential, a calcium‐activated chloride Cl(Ca) determines plateau phase inwardly rectifying potassium Kir important generation resting...