A5067887768- Cellular transport and secretion
- Neuroscience and Neuropharmacology Research
- Genetics and Neurodevelopmental Disorders
- RNA regulation and disease
- Lipid Membrane Structure and Behavior
- Connexins and lens biology
- Retinal Development and Disorders
- Single-cell and spatial transcriptomics
- Genetic Neurodegenerative Diseases
- Statistical Methods in Clinical Trials
- Neuroscience and Neural Engineering
- Mitochondrial Function and Pathology
- Statistical Methods and Inference
- Congenital heart defects research
- Cardiac electrophysiology and arrhythmias
- Gene expression and cancer classification
- Autism Spectrum Disorder Research
Amsterdam Neuroscience
2017-2025
Vrije Universiteit Amsterdam
2020-2025
Cancer Genomics Centre
2022
Amsterdam University Medical Centers
2021-2022
University of Amsterdam
2021
Amsterdam UMC Location Vrije Universiteit Amsterdam
2019
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...
Disease-causing variants in STXBP1 are among the most common genetic causes of neurodevelopmental disorders. However, phenotypic spectrum STXBP1-related disorders is wide and clear correlations between variant type clinical features have not been observed so far. Here, we harmonized data across 534 individuals with analysed 19 973 derived terms, including phenotypes 253 previously unreported scientific literature. The overall landscape characterized by abnormalities 95% seizures 89%...
Heterozygous mutations in the STXBP1 gene encoding presynaptic protein MUNC18-1 cause encephalopathy, characterized by developmental delay, intellectual disability and epilepsy. Impaired mutant stability leading to reduced synaptic transmission is considered main underlying pathogenetic mechanism. Here, we report first two cases carrying a homozygous mutation, where their heterozygous siblings mother are asymptomatic. Both were diagnosed with Lennox-Gastaut syndrome. In Munc18-1 null mouse...
Abstract Studies using induced pluripotent stem cells (iPSCs) are gaining momentum in brain disorder modelling, but optimal study designs poorly defined. Here, we compare commonly used and statistical analysis for different research aims. Furthermore, generated immunocytochemical, electrophysiological, proteomic data from iPSC-derived neurons of five healthy subjects, analysed variation conducted power simulations. These analyses show that published case–control iPSC studies generally...
Tyrosine kinases are important regulators of synaptic strength. Here, we describe a key component the vesicle release machinery, Munc18-1, as phosphorylation target for neuronal Src family (SFKs). Phosphomimetic Y473D mutation SFK site previously identified by brain phospho-proteomics abolished stimulatory effect Munc18-1 on SNARE complex formation ("SNARE-templating") and membrane fusion in vitro Furthermore, priming but not docking vesicles was disrupted hippocampal munc18-1-null neurons...
STXBP1 syndrome is a rare neurodevelopmental disorder caused by heterozygous variants in the gene and characterized psychomotor delay, early-onset developmental epileptic encephalopathy. Pathogenic are thought to alter excitation-inhibition (E/I) balance at synaptic level, which could impact neuronal network dynamics; however, this has not been investigated yet. Here, we present first EEG study of patients with quantify E/I dysregulation on ongoing brain activity. We used...
Changes in excitation and inhibition are associated with the pathobiology of neurodevelopmental disorders intellectual disability autism, widely described Fragile X syndrome (FXS). In prefrontal cortex (PFC), essential for cognitive processing, excitatory connectivity plasticity is found altered FXS mouse model, however, little known about state inhibition. To that end, we investigated GABAergic signalling Mental Retardation 1 knock out (Fmr1-KO) medial PFC (mPFC). We report changes at...
SNAREopathies constitute a group of severe genetic neurodevelopmental disorders caused by de novo variants that disturb the synaptic release machinery. These comprise highly diverse clinical phenotypes, usually including developmental delay, epilepsy, intellectual disability, and sometimes autism spectrum disorder. Despite major progress in testing, current treatments are limited to symptom-directed therapies. There is an urgent need establish human experimental systems improve...
<title>Abstract</title> Brain disorders caused by large effect mutations in single genes often present unexplained phenotypic diversity, even among carriers of the same mutation. Here we examined genetic interactions as a possible explanation for this diversity SNAREopathies, group neurodevelopmental <italic>de novo</italic> variation that together drive secretion chemical signals brain. SNAREopathies are characterized striking including different types/degrees or absence seizures,...
Absence of presynaptic protein MUNC18-1 (gene:
MUNC18-1 (also known as syntaxin-binding protein-1, encoded by Stxbp1) binds to syntaxin-1. Together, these proteins regulate synaptic vesicle exocytosis and have a separate role in neuronal viability. In Stxbp1 null mutant neurons, syntaxin-1 protein levels are reduced 70%. Here, we show that dynamin-1 at least the same extent, transcript of Dnm1 (which encodes dynamin-1) 50% brain. Several, but not all, other endocytic were also found be reduced, lesser extent. The expression was observed...