Virtual and experimental approaches to the pathogenicity of SynGAP1 missense mutations
Targeting gamma oscillations to improve cognition
SYNGAP1 Natural History Study/ Multidisciplinary Clinic at Children’s Hospital Colorado
Beyond the synapse: SYNGAP1 in primary and motile cilia
The Roles of Distinct Functions of SynGAP1 in SYNGAP1-Related Disorders
Activity-Dependent Gene Regulation in Health and Disease
In the last of this year’s Brain Prize webinars, Elizabeth Pollina (Washington University, USA), Eric Nestler (Icahn School of Medicine Mount Sinai, USA) and Michelle Monje (Stanford University, USA) will present their work on activity-dependent gene regulation in health and disease. Each speaker will present for 25 minutes, and the webinar will conclude with an open discussion. The webinar will be moderated by the winners of the 2023 Brain Prize, Michael Greenberg, Erin Schuman and Christine Holt.
Dysfunctional translation in disease
In the fifth of this year’s Brain Prize webinars, Emily Osterweil (Harvard Medical School, USA), Gary Bassell (Emory University, USA) and Giovanna Mallucci (Altos Labs, UK) will present their work on dysfunctional translation in disease. Each speaker will present for 25 minutes, and the webinar will conclude with an open discussion. The webinar will be moderated by two of the winners of the 2023 Brain Prize, Michael Greenberg and Erin Schuman.
Quantifying perturbed SynGAP1 function caused by coding mutations
Restoring function in advanced disease with photoreceptor cell replacement therapy
Therapeutic Strategies for Autism: Targeting Three Levels of the Central Dogma of Molecular Biology with a Focus on SYNGAP1
Involvement of the brain endothelium in neurodevelopmental disorders
Catatonia in Neurodevelopmental Conditions
A Data-Driven Approach to Reconstructing Disease Trajectories in SYNGAP1-Related Disorders
Harnessing mRNA metabolism for the development of precision gene therapy
Linking SYNGAP1 with Human-Specific Mechanisms of Neuronal Development
SYNGAP1 and Epilepsy SurgerySYNGAP1 and Epilepsy Surgery
Targeting alternative splicing of SYNGAP1 using antisense oligonucleotides
Cognitive Maps
Ample evidence suggests that the brain generates internal simulations of the outside world to guide our thoughts and actions. These mental representations, or cognitive maps, are thought to be essential for our very comprehension of reality. I will discuss what is known about the informational structure of cognitive maps, their neural underpinnings, and how they relate to behavior, evolution, disease, and the current revolution in artificial intelligence.
The use of milk exosomes to increase the expression of SYNGAP1 expression in SYNGAP1 mice
An Introduction to Autism BrainNet
Investigating the functional single-cell biology of SynGAP1 pathways
Relearning to see with a damaged V1
Interpretation of SYNGAP1 Variants
Improving the assessment of SYNGAP1 and related genetic conditions by creating online measures for parents and patients
SynGAP modulates the body's biological clock: What Syngap1 mice can tell us about light & sleep
Types of seizures and EEG patterns in SYNGAP1
Modulating gene regulation to treat gene dosage-associated diseases
Sensory brain responses alterations as translational markers for SynGAP1 haploinsufficiency
Cómo y por qué utilizar modelos celulares humanos para estudiar Syngap1
Alteraciones en los patrones electrofisiológicos subyacentes a la percepción sensorial y su uso como biomarcadores de Syngap1
Interpretación de variantes en SYNGAP1
Desarrollo de tratamientos para síndromes de epilepsia: oportunidades para SYNGAP1
Alteraciones moleculares en el proteoma sináptico causadas por la deficiencia de SYNGAP1
Proyecto: Registro español SYNGAP1 - historia natural y estudio del sueño, Share4Rareplatform
El ABA (análisis aplicado de la conducta) y su contribución a la sustracción de servicios para el desarrollo de habilidades
Mitos y verdades en el manejo de las encefalopatías epilépticas: experiencia en Colombia
Encefalopatías epilépticas: experiencia diagnóstica de un grupo de la ciudad de Medellín
Tipos de crisis epilépticas y patrones en electroencefalografía en SYNGAP1
Características generales de la encefalopatía epiléptica y desarrollo en SYNGAP1
Behavioural and cellular pathophysiology in a rat model of SYNGAP1 haploinsufficiency
Cannabinoids: What do we know
Cognition, behaviour and clinical trials in SYNGAP1
SYNGAP1 in translation: from deep phenotyping to human neurons
SYNGAP1 in the Developing Human Cortex
Progenitor mechanisms and cerebral cortical malformations'
How and why to use human cellular models to study SYNGAP1
Studying cortical development through the lens of human disorders
SYNGAP1: The road from gene discovery to targeted therapy
A decade of TMEM106B research
Towards therapeutics for Autism Spectrum Disorder using Syngap1 heterozygous mouse model
Rescue of SynGAP expression in SYNGAP1 Syndrome: Antisense Oligonucleotides (ASOs), small molecules, & viral genetic rescue
Leveraging technology to improve access to rare disease research
Autism-Associated Shank3 Is Essential for Homeostatic Compensation in Rodent Visual Cortex
Neocortical networks must generate and maintain stable activity patterns despite perturbations induced by learning and experience- dependent plasticity. There is abundant theoretical and experimental evidence that network stability is achieved through homeostatic plasticity mechanisms that adjust synaptic and neuronal properties to stabilize some measure of average activity, and this process has been extensively studied in primary visual cortex (V1), where chronic visual deprivation induces an initial drop in activity and ensemble average firing rates (FRs), but over time activity is restored to baseline despite continued deprivation. Here I discuss recent work from the lab in which we followed this FR homeostasis in individual V1 neurons in freely behaving animals during a prolonged visual deprivation/eye-reopening paradigm. We find that - when FRs are perturbed by manipulating sensory experience - over time they return precisely to a cell-autonomous set-point. Finally, we find that homeostatic plasticity is perturbed in a mouse model of Autism spectrum disorder, and this results in a breakdown of FRH within V1. These data suggest that loss of homeostatic plasticity is one primary cause of excitation/inhibition imbalances in ASD models. Together these studies illuminate the role of stabilizing plasticity mechanisms in the ability of neocortical circuits to recover robust function following challenges to their excitability.
Neural circuit redundancy, stability, and variability in developmental brain disorders
Despite the consistency of symptoms at the cognitive level, we now know that brain disorders like Autism and Schizophrenia can each arise from mutations in >100 different genes. Presumably there is a convergence of “symptoms” at the level of neural circuits in diagnosed individuals. In this talk I will argue that redundancy in neural circuit parameters implies that we should take a circuit-function rather that circuit-component approach to understanding these disorders. Then I will present our recent empirical work testing a circuit-function theory for Autism: the idea that neural circuits show excess trial-to-trial variability in response to sensory stimuli, and instability in the representations across a timescale of days. For this we analysed in vivo neural population activity data recorded from somatosensory cortex of mouse models of Fragile-X syndrome, a disorder related to autism. Work with Beatriz Mizusaki (Univ of Bristol), Nazim Kourdougli, Anand Suresh, and Carlos Portera-Cailliau (Univ of California, Los Angeles).
Watching single molecules in action: How this can be used in neurodegeneration
This talk aims to show how new physical methods can advance biological and biomedical research. A major advance in physical chemistry in the last two decades has been the development of quantitative methods to directly observe individual molecules in solution, attached to surfaces, in the membrane of live cells or more recently inside live cells. These single-molecule fluorescence studies have now reached a stage where they can provide new insights into important biological problems. After presenting the principles of these methods, I will give some examples from our current research to probe the molecular basis of neurodegeneration. Here we have used single-molecule fluorescence to detect and analyse the low concentrations of soluble protein aggregates thought to be responsible for Alzheimer’s disease and determine the mechanisms by which they damage neurons. Lastly, I will describe how fundamental science aimed at watching single molecules incorporating nucleotides into DNA gave rise to a new rapid method to sequence DNA that is now widely used.
Cellular/circuit dysfunction in a model of Dravet syndrome - a severe childhood epilepsy
Dravet syndrome is a severe childhood epilepsy due to heterozygous loss-of-function mutation of the gene SCN1A, which encodes the type 1 neuronal voltage gated sodium (Na+) channel alpha-subunit Nav1.1. Prior studies in mouse models of Dravet syndrome (Scn1a+/- mice) at early developmental time points indicate that, in cerebral cortex, Nav1.1 is predominantly expressed in GABAergic interneurons (INs) and, in particular, in parvalbumin-positive fast-spiking basket cells (PV-INs). This has led to a model of Dravet syndrome pathogenesis whereby Nav1.1 mutation leads to preferential IN dysfunction, decreased synaptic inhibition, hyperexcitability, and epilepsy. We found that, at later developmental time points, the intrinsic excitability of PV-INs has essentially normalized, via compensatory reorganization of axonal Na+ channels. Instead, we found persistent and seemingly paradoxical dysfunction of putative disinhibitory INs expressing vasoactive intestinal peptide (VIP-INs). In vivo two-photon calcium imaging in neocortex during temperature-induced seizures in Scn1a+/- mice showed that mean activity of both putative principal cells and PV-INs was higher in Scn1a+/- relative to wild-type controls during quiet wakefulness at baseline and at elevated core body temperature. However, wild-type PV-INs showed a progressive synchronization in response to temperature elevation that was absent in PV-INs from Scn1a+/- mice immediately prior to seizure onset. We suggest that impaired PV-IN synchronization, perhaps via persistent axonal dysfunction, may contribute to the transition to the ictal state during temperature induced seizures in Dravet syndrome.