This work can be found here
Synapses are specialized structures in the brain, connecting neurons with each other and allowing them to exchange signals rapidly. Several diseases such as autism and schizophrenia spectrum disorders can be linked to changes in synapses at the protein level, that arise during development. By bringing scientific information together in a systematic knowledgebase, SynGO allows researchers around the world to learn more about underlying disease mechanisms.
The user-friendly website syngoportal.org enables advanced analyses and intuitive visualization tools that contribute to the popularity of the platform. Every month the website has thousands of pageviews, resulting in analyses and graphics that are used in high-impact publications.
Currently the consortium is working on phase 2 of the project, annotating direct interactions between synaptic proteins, which is scheduled for release in 2024. In the long term the ambition is to also describe causal relationships of biological functions and systems in the synapse.
AUMC and VU have worked together with industry to develop animal and human disease models for STXBP1-RD and to design and test new therapies. In parallel, ESCO aims to prepare the field for successful and efficient evaluation of new therapies for STXBP1-RD and promote equal and evidence-based access to new therapies. Starting Q1 2024, ESCO will direct a natural history study (NHS) in eight EU sites + Israel. ESCO has secured its first funding from the international STXBP1 foundation. Several letters of intent have been signed by pioneer sponsors (industry). In parallel, ESCO has applied for the Innovative Tools program at EMA to be able to exploit the NHS as a concurrent control arm for future clinical trials.
The STXBP1 gene lies on Chromosome 9. Therefore, the ninth month, September, was named STXBP1 awareness month.
Our team at the FGA department wanted to mark this month with a social outreach event. We baked more than 250 cookies in STXBP1 shape and distributed them across the campus of the VU. This video shows the process of the baking and distributing and introduces the members of our team and the topics of their research into understanding STXBP1 disorder.
NEDERLANDS
Het STXBP1-gen ligt op chromosoom 9. Daarom werd de negende maand, september, de STXBP1-bewustzijnsmaand genoemd.
Ons team op de FGA-afdeling wilde deze maand markeren met een social outreach-evenement. We bakten ruim 250 koekjes in STXBP1-vorm en verdeelden deze over de campus van de VU. Deze video toont het proces van het bakken en distribueren en introduceert de leden van ons team en de onderwerpen van hun onderzoek naar het begrijpen van de STXBP1-stoornis.
In a suite of 21 papers (https://www.science.org/) published on 12 October in special issues of Science, Science Advances, and Science Translational Medicine, the consortium of researchers, brought together by the National Institutes of Health’s BRAIN Initiative Cell Census Network program, shares new knowledge about the cells that make up our brains and the brains of other primates. INF contributed to four papers in this package: two published in Science and two papers form Goriounova team published in Science Advances. It’s a huge leap from previously published work, with studies and data that reveal new insights about our nervous systems’ cellular makeup across many regions of the brain and what is distinctive about the human brain.
To characterize brain cells, the molecular signature of gene expression was determined for each cell separately using spatial transcriptomic and snRNA sequencing techniques. The data from the newly released studies will also feed into the Human Cell Atlas, an international effort that is building a comprehensive reference atlas of cells across all organs, tissues, and systems of the human body.
Cell types human temporal cortex
Studying human brain cells in living human brain tissue can only takes place in a limited number of places in the world. It requires close collaboration between neuroscientists and the neurosurgery department, where surgical treatment of epilepsy and tumor patients takes place. In order to study sufficient brain material for the research, laboratories from different countries participated, including Goriounova, Mansvelder and de Kock teams. The studies to which our teams contributed went a step further by studying the consequences of gene expression for cell shape and function of the mapped cell types. The studies show that human temporal cortex, this evolutionarily developed part of the human brain, contains cell types that have distinct functional properties and transcriptomic signature, not seen in mice. The fast functional properties of human cells enable human circuits to remain fast despite large neuron-to-neuron distances in the expanded human brain.
Axon Initial Segment (AIS) plasticity is a crucial process for neuronal homeostasis, as it allows neurons to adapt action potentials output to changes in network activity. The initiation and shape of action potential initiation relies on the clustering of voltage-gated sodium channels at the AIS, but how those channels reorganize during plasticity remain largely elusive.
In this study, we have engineered genetic tools to label endogenous sodium channels and their associated scaffolding proteins. This approach allowed us to uncover their nanoscale organization and longitudinally image AIS plasticity in hippocampal neurons.
Our results reveal that NMDA receptors activation triggers both synaptic depression and AIS plasticity. Notably, the distal pool of sodium channels is endocytosed, and this reduction in AIS length is associated with a decrease in neuronal excitability.
Our data reveal a fundamental mechanism for rapid activity-dependent AIS reorganization and suggests that plasticity of intrinsic excitability shares conserved features with synaptic plasticity.
The paper can be found here
The balance between excitatory (E) and inhibitory (I) signaling is crucial for proper brain development and functioning. Indeed, alterations in E/I balance supposedly underlie clinical manifestations of neurodevelopmental disorders ranging from behavioral disturbances to seizures. Many existing and new pharmacological interventions target elements of E/I-balance regulation; however, lack of technology to track changes in E/I ratio that is clinically insightful is limiting their implementation. In the BRAINinBALANCE public-private partnership between the N=You Neurodevelopmental Precision Center at Amsterdam UMC and MedTech company Clouds of Care, we aim to solve this problem.
Specifically, based on our patent-pending algorithm to quantify network-level E/I ratio directly from EEG signals (Bruining et al., 2020), we will build a standardized EEG analysis workflow for individual-subject monitoring of E/I regulation through pharmacological interventions. This includes different anti-epileptic drugs, which is the focus area of Epilog, a brand of Clouds of Care, and bumetanide treatment of children with autism spectrum disorder that have participated in a large EEG-assisted trial at the N = You Neurodevelopmental Precision Center. When successful, the knowledge and methods could be applied to other brain disorders currently investigated for E/I dysregulation, such as Alzheimer’s disease, Schizophrenia, and depression.
References
Bruining H, Hardstone R, Juarez-Martinez E, Sprengers J, Avramiea A-E, Simpraga S, Houtman SJ, Poil S-S, Dallares E, Palva S, Oranje B, Palva JM, Mansvelder HD, Linkenkaer-Hansen K. Measurement of excitation/inhibition ratio in autism spectrum disorder using critical brain dynamics. Scientific Reports; 1–15, 2020. https://doi.org/10.1038/s41598-020-65500-4
Is uw kind 6 jaar of ouder met diagnose van STXBP1 encefalopathie? Dan komt hij/zij vermoedelijk in aanmerking voor deze studie. Een kort overzicht van de studie vindt u in de onderstaande afbeelding. De reiskosten naar Antwerpen worden vergoed en we kunnen de twee studiebezoeken op 1 dag combineren als dit makkelijker is. Interesse? Bespreek dit met je behandelend arts en neem contact op met Hanna Stamberger (hannah.stamberger@uantwerpen.be) voor meer informatie.
In the study Libedinsky and co authors Y. Wei, C.A. de Leeuw, J. Rilling, D. Posthuma and M.P. van den Heuvel combined data from genome-wide association studies on human phenotypes traits with estimates of human genome dating. They systematically analyzed the temporal emergence of genetic variants associated with modern-day human brain and cognitive phenotypes over the last five million years. The researchers found that the emergence of genetic variants associated with core human attributes, such as brain morphology, cognition, and neuropsychiatric conditions, follows a distinctive temporal pattern, revealing recent genetic modifications in human evolution.
More information:
ISIR conference
Article Genetic timeline of human brain and cognitive traits https://www.biorxiv.org/content/10.1101/2023.02.05.525539v1
CNCR researcher Ilan Libedinsky