Publications by authors named "Hanna Lammertse"
Article Synopsis
- The study investigates a neurodevelopmental disorder (-RD) caused by mutations in the MUNC18-1 gene, leading to symptoms like developmental delay and seizures, with varying severity among patients.
- Using advanced techniques, researchers analyzed neurons derived from patients' stem cells, finding reduced levels of the MUNC18-1 protein, along with dysregulated proteins linked to synapse function and altered neuronal network activity.
- The findings reveal common cellular traits across patients with -RD while also highlighting distinct phenotypic differences, suggesting varied underlying mechanisms of the disorder that could inform future research and therapy development.
Article Synopsis
- Induced pluripotent stem cells (iPSCs) are increasingly used for modeling brain disorders, but there's a lack of clarity on the best study designs and statistical analyses.
- The researchers compared different study designs, generating various types of data from iPSC-derived neurons, and found that many existing studies are underpowered.
- They discovered that using isogenic iPSC lines offers more statistical power compared to traditional case-control designs and introduced a free online tool to help researchers optimize study designs based on preliminary data.
Article Synopsis
- * In Stxbp1 null mutants, dynamin-1 levels drop significantly, and the transcript levels of its encoding gene, Dnm1, are also reduced by 50%, impacting several other endocytic proteins to a lesser degree.
- * The study indicates that MUNC18-1 does not directly bind dynamin-1, and reducing dynamin-1 alone doesn’t cause neurodegeneration in Stxbp1 mutants, suggesting that MUNC18-1
Article Synopsis
- * A majority of participants exhibit neurodevelopmental issues (95%) and seizures (89%), with common seizure types and early onset, underscoring the severity of STXBP1-related conditions.
- * Despite identifying frequent genetic variants, no specific associations were found between these variants and particular clinical syndromes, indicating a high level of variability in the clinical presentation of STXBP1-related disorders.
syndrome is a rare neurodevelopmental disorder caused by heterozygous variants in the gene and is characterized by psychomotor delay, early-onset developmental delay, and epileptic encephalopathy. Pathogenic variants are thought to alter excitation-inhibition (E/I) balance at the synaptic level, which could impact neuronal network dynamics; however, this has not been investigated yet. Here, we present the first EEG study of patients with syndrome to quantify the impact of the synaptic E/I dysregulation on ongoing brain activity.
View Article and Find Full Text PDFChanges in excitation and inhibition are associated with the pathobiology of neurodevelopmental disorders of intellectual disability and autism and are widely described in Fragile X syndrome (FXS). In the prefrontal cortex (PFC), essential for cognitive processing, excitatory connectivity and plasticity are found altered in the FXS mouse model, however, little is known about the state of inhibition. To that end, we investigated GABAergic signaling in the Fragile X Mental Retardation 1 (FMR1) knock out (Fmr1-KO) mouse medial PFC (mPFC).
View Article and Find Full Text PDFHeterozygous mutations in the STXBP1 gene encoding the presynaptic protein MUNC18-1 cause STXBP1 encephalopathy, characterized by developmental delay, intellectual disability and epilepsy. Impaired mutant protein stability leading to reduced synaptic transmission is considered the main underlying pathogenetic mechanism. Here, we report the first two cases carrying a homozygous STXBP1 mutation, where their heterozygous siblings and mother are asymptomatic.
View Article and Find Full Text PDFSynaptic 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.
View Article and Find Full Text PDFTyrosine kinases are important regulators of synaptic strength. Here, we describe a key component of the synaptic vesicle release machinery, Munc18-1, as a phosphorylation target for neuronal Src family kinases (SFKs). Phosphomimetic Y473D mutation of a SFK phosphorylation site previously identified by brain phospho-proteomics abolished the stimulatory effect of Munc18-1 on SNARE complex formation ("SNARE-templating") and membrane fusion Furthermore, priming but not docking of synaptic vesicles was disrupted in hippocampal -null neurons expressing Munc18-1 Synaptic transmission was temporarily restored by high-frequency stimulation, as well as by a Munc18-1 mutation that results in helix 12 extension, a critical conformational step in vesicle priming.
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