Cellular Crosstalk in Brain Development, Evolution and Disease

Cellular crosstalk is an essential process during brain development and is influenced by numerous factors, including cell morphology, adhesion, the local extracellular matrix and secreted vesicles. Inspired by mutations associated with neurodevelopmental disorders, we focus on understanding the role of extracellular mechanisms essential for the proper development of the human brain. Therefore, we combine 2D and 3D in vitro human models to better understand the molecular and cellular mechanisms involved in progenitor proliferation and fate, migration and maturation of excitatory and inhibitory neurons during human brain development and tackle the causes of neurodevelopmental disorders.

Gene regulatory mechanisms of neocortex development and evolution

The neocortex is considered to be the seat of higher cognitive functions in humans. During its evolution, most notably in humans, the neocortex has undergone considerable expansion, which is reflected by an increase in the number of neurons. Neocortical neurons are generated during development by neural stem and progenitor cells. Epigenetic mechanisms play a pivotal role in orchestrating the behaviour of stem cells during development. We are interested in the mechanisms that regulate gene expression in neural stem cells, which have implications for our understanding of neocortex development and evolution, neural stem cell regulation and neurodevelopmental disorders.

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

Modeling human brain development and disease: the role of primary cilia

Neurodevelopmental disorders (NDDs) impose a global burden, affecting an increasing number of individuals. While some causative genes have been identified, understanding the human-specific mechanisms involved in these disorders remains limited. Traditional gene-driven approaches for modeling brain diseases have failed to capture the diverse and convergent mechanisms at play. Centrosomes and cilia act as intermediaries between environmental and intrinsic signals, regulating cellular behavior. Mutations or dosage variations disrupting their function have been linked to brain formation deficits, highlighting their importance, yet their precise contributions remain largely unknown. Hence, we aim to investigate whether the centrosome/cilia axis is crucial for brain development and serves as a hub for human-specific mechanisms disrupted in NDDs. Towards this direction, we first demonstrated species-specific and cell-type-specific differences in the cilia-genes expression during mouse and human corticogenesis. Then, to dissect their role, we provoked their ectopic overexpression or silencing in the developing mouse cortex or in human brain organoids. Our findings suggest that cilia genes manipulation alters both the numbers and the position of NPCs and neurons in the developing cortex. Interestingly, primary cilium morphology is disrupted, as we find changes in their length, orientation and number that lead to disruption of the apical belt and altered delamination profiles during development. Our results give insight into the role of primary cilia in human cortical development and address fundamental questions regarding the diversity and convergence of gene function in development and disease manifestation. It has the potential to uncover novel pharmacological targets, facilitate personalized medicine, and improve the lives of individuals affected by NDDs through targeted cilia-based therapies.

Contrasting developmental principles of human brain development and their relevance to neurodevelopmental disorders

Predictive processing: a circuit approach to psychosis

Predictive processing is a computational framework that aims to explain how the brain processes sensory information by making predictions about the environment and minimizing prediction errors. It can also be used to explain some of the key symptoms of psychotic disorders such as schizophrenia. In my talk, I will provide an overview of our progress in this endeavor.

Cortical interneurons from brain development to disease

Cellular crosstalk in Neurodevelopmental Disorders

Cellular crosstalk is an essential process during brain development and it is influenced by numerous factors, including the morphology of the cells, their adhesion molecules, the local extracellular matrix and the secreted vesicles. Inspired by mutations associated with neurodevelopmental disorders, we focus on understanding the role of extracellular mechanisms essential for the correct development of the human brain. Hence, we combine the in vivo mouse model and the in vitro human-derived neurons, cerebral organoids, and dorso-ventral assembloids in order to better comprehend the molecular and cellular mechanisms involved in ventral progenitors’ proliferation and fate as well as migration and maturation of inhibitory neurons during human brain development and tackle the causes of neurodevelopmental disorders. We particularly focus on mutations in genes influencing cell-cell contacts, extracellular matrix, and secretion of vesicles and therefore study intrinsic and extrinsic mechanisms contributing to the formation of the brain. Our data reveal an important contribution of cell non-autonomous mechanisms in the development of neurodevelopmental disorders.

Movement planning as a window into hierarchical motor control

The ability to organise one's body for action without having to think about it is taken for granted, whether it is handwriting, typing on a smartphone or computer keyboard, tying a shoelace or playing the piano. When compromised, e.g. in stroke, neurodegenerative and developmental disorders, the individuals’ study, work and day-to-day living are impacted with high societal costs. Until recently, indirect methods such as invasive recordings in animal models, computer simulations, and behavioural markers during sequence execution have been used to study covert motor sequence planning in humans. In this talk, I will demonstrate how multivariate pattern analyses of non-invasive neurophysiological recordings (MEG/EEG), fMRI, and muscular recordings, combined with a new behavioural paradigm, can help us investigate the structure and dynamics of motor sequence control before and after movement execution. Across paradigms, participants learned to retrieve and produce sequences of finger presses from long-term memory. Our findings suggest that sequence planning involves parallel pre-ordering of serial elements of the upcoming sequence, rather than a preparation of a serial trajectory of activation states. Additionally, we observed that the human neocortex automatically reorganizes the order and timing of well-trained movement sequences retrieved from memory into lower and higher-level representations on a trial-by-trial basis. This echoes behavioural transfer across task contexts and flexibility in the final hundreds of milliseconds before movement execution. These findings strongly support a hierarchical and dynamic model of skilled sequence control across the peri-movement phase, which may have implications for clinical interventions.

Quantifying perturbed SynGAP1 function caused by coding mutations

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

Circuit mechanisms of attention dysfunction in Scn8a+/- mice: implications for epilepsy and neurodevelopmental disorders

The balanced brain: two-photon microscopy of inhibitory synapse formation

Coordination between excitatory and inhibitory synapses (providing positive and negative signals respectively) is required to ensure proper information processing in the brain. Many brain disorders, especially neurodevelopental disorders, are rooted in a specific disturbance of this coordination. In my research group we use a combination of two-photon microscopy and electrophisiology to examine how inhibitory synapses are fromed and how this formation is coordinated with nearby excitatroy synapses.

Catatonia in Neurodevelopmental Conditions

Precision Genomics in Neurodevelopmental Disorders

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

Myelin Formation and Oligodendrocyte Biology in Epilepsy

Epilepsy is one of the most common neurological diseases according to the World Health Organization (WHO) affecting around 70 million people worldwide [WHO]. Patients who suffer from epilepsy also suffer from a variety of neuro-psychiatric co-morbidities, which they can experience as crippling as the seizure condition itself. Adequate organization of cerebral white matter is utterly important for cognitive development. The failure of integration of neurologic function with cognition is reflected in neuro-psychiatric disease, such as autism spectrum disorder (ASD). However, in epilepsy we know little about the importance of white matter abnormalities in epilepsy-associated co-morbidities. Epilepsy surgery is an important therapy strategy in patients where conventional anti-epileptic drug treatment fails . On histology of the resected brain samples, malformations of cortical development (MCD) are common among the epilepsy surgery population, especially focal cortical dysplasia (FCD) and tuberous sclerosis complex (TSC). Both pathologies are associated with constitutive activation of the mTOR pathway. Interestingly, some type of FCD is morphological similar to TSC cortical tubers including the abnormalities of the white matter. Hypomyelination with lack of myelin-producing cells, the oligodendrocytes, within the lesional area is a striking phenomenon. Impairment of the complex myelination process can have a major impact on brain function. In the worst case leading to distorted or interrupted neurotransmissions. It is still unclear whether the observed myelin pathology in epilepsy surgical specimens is primarily related to the underlying malformation process or is just a secondary phenomenon of recurrent epileptic seizures creating a toxic micro-environment which hampers myelin formation. Interestingly, mTORC1 has been implicated as key signal for myelination, thus, promoting the maturation of oligodendrocytes . These results, however, remain controversial. Regardless of the underlying pathophysiologic mechanism, alterations of myelin dynamics, depending on their severity, are known to be linked to various kinds of developmental disorders or neuropsychiatric manifestations.

SYNGAP1 and Epilepsy SurgerySYNGAP1 and Epilepsy Surgery

Children-Agent Interaction For Assessment and Rehabilitation: From Linguistic Skills To Mental Well-being

Socially Assistive Robots (SARs) have shown great potential to help children in therapeutic and healthcare contexts. SARs have been used for companionship, learning enhancement, social and communication skills rehabilitation for children with special needs (e.g., autism), and mood improvement. Robots can be used as novel tools to assess and rehabilitate children’s communication skills and mental well-being by providing affordable and accessible therapeutic and mental health services. In this talk, I will present the various studies I have conducted during my PhD and at the Cambridge Affective Intelligence and Robotics Lab to explore how robots can help assess and rehabilitate children’s communication skills and mental well-being. More specifically, I will provide both quantitative and qualitative results and findings from (i) an exploratory study with children with autism and global developmental disorders to investigate the use of intelligent personal assistants in therapy; (ii) an empirical study involving children with and without language disorders interacting with a physical robot, a virtual agent, and a human counterpart to assess their linguistic skills; (iii) an 8-week longitudinal study involving children with autism and language disorders who interacted either with a physical or a virtual robot to rehabilitate their linguistic skills; and (iv) an empirical study to aid the assessment of mental well-being in children. These findings can inform and help the child-robot interaction community design and develop new adaptive robots to help assess and rehabilitate linguistic skills and mental well-being in children.

Developmental disorders of presynaptic vesicle cycling - Synaptotagmin-1 and beyond

Post-diagnostic research on rare genetic developmental disorders presents new opportunities (and a few challenges) for discovery neuroscience and translation. In this talk, Kate will describe and discuss neurodevelopmental phenotypes arising from rare, high penetrance genomic variants which directly influence pre-synaptic vesicle cycling (SVC disorders). She will focus on Synaptotagmin-1 Associated Neurodevelopmental Disorder (also known as Baker Gordon Syndrome), first described in 2015 and now diagnosed in more than 50 children and young people worldwide. She will then present work-in-progress by her group on the neurodevelopmental spectrum of SVC disorders more broadly, and discuss opportunities for collaborative neuroscience which can bridge the gaps between genetic cause and complex neurological, cognitive and mental health outcomes.

Baby steps to breakthroughs in precision health in neurodevelopmental disorders

Myelin Formation and Oligodendrocyte Biology in Epilepsy

Epilepsy is one of the most common neurological diseases according to the World Health Organization (WHO) affecting around 70 million people worldwide [WHO]. Patients who suffer from epilepsy also suffer from a variety of neuro-psychiatric co-morbidities, which they can experience as crippling as the seizure condition itself. Adequate organization of cerebral white matter is utterly important for cognitive development. The failure of integration of neurologic function with cognition is reflected in neuro-psychiatric disease, such as autism spectrum disorder (ASD). However, in epilepsy we know little about the importance of white matter abnormalities in epilepsy-associated co-morbidities. Epilepsy surgery is an important therapy strategy in patients where conventional anti-epileptic drug treatment fails . On histology of the resected brain samples, malformations of cortical development (MCD) are common among the epilepsy surgery population, especially focal cortical dysplasia (FCD) and tuberous sclerosis complex (TSC). Both pathologies are associated with constitutive activation of the mTOR pathway. Interestingly, some type of FCD is morphological similar to TSC cortical tubers including the abnormalities of the white matter. Hypomyelination with lack of myelin-producing cells, the oligodendrocytes, within the lesional area is a striking phenomenon. Impairment of the complex myelination process can have a major impact on brain function. In the worst case leading to distorted or interrupted neurotransmissions. It is still unclear whether the observed myelin pathology in epilepsy surgical specimens is primarily related to the underlying malformation process or is just a secondary phenomenon of recurrent epileptic seizures creating a toxic micro-environment which hampers myelin formation. Interestingly, mTORC1 has been implicated as key signal for myelination, thus, promoting the maturation of oligodendrocytes . These results, however, remain controversial. Regardless of the underlying pathophysiologic mechanism, alterations of myelin dynamics, depending on their severity, are known to be linked to various kinds of developmental disorders or neuropsychiatric manifestations.

Targeting alternative splicing of SYNGAP1 using antisense oligonucleotides

Functional and translational implications of A-to-I editing in brain development and neurodevelopmental disorders

Investigating activity-dependent processes in cerebral cortex development and disease

The cerebral cortex contains an extraordinary diversity of excitatory projection neuron (PN) and inhibitory interneurons (IN), wired together to form complex circuits. Spatiotemporally coordinated execution of intrinsic molecular programs by PNs and INs and activity-dependent processes, contribute to cortical development and cortical microcircuits formation. Alterations of these delicate processes have often been associated to neurological/neurodevelopmental disorders. However, despite the groundbreaking discovery that spontaneous activity in the embryonic brain can shape regional identities of distinct cortical territories, it is still unclear whether this early activity contributes to define subtype-specific neuronal fate as well as circuit assembly. In this study, we combined in utero genetic perturbations via CRISPR/Cas9 system and pharmacological inhibition of selected ion channels with RNA-sequencing and live imaging technologies to identify the activity-regulated processes controlling the development of different cortical PN classes, their wiring and the acquisition of subtype specific features. Moreover, we generated human induced pluripotent stem cells (iPSCs) form patients affected by a severe, rare and untreatable form of developmental epileptic encephalopathy. By differentiating cortical organoids form patient-derived iPSCs we create human models of early electrical alterations for studying molecular, structural and functional consequences of the genetic mutations during cortical development. Our ultimate goal is to define the activity-conditioned processes that physiologically occur during the development of cortical circuits, to identify novel therapeutical paths to address the pathological consequences of neonatal epilepsies.

Don't forget the gametes: Neurodevelopmental pathogenesis starts in the sperm and egg

Proper development of the nervous system depends not only on the inherited DNA sequence, but also on proper regulation of gene expression, as controlled in part by epigenetic mechanisms present in the parental gametes. In this presentation an internationally recognized research advocate explains why researchers concerned about the origins of increasingly prevalent neurodevelopmental disorders such as autism and attention deficit hyperactivity disorder should look beyond genetics in probing the origins of dysregulated transcription of brain-related genes. The culprit for a subset of cases, she contends, may lie in the exposure history of the parents, and thus their germ cells. To illustrate how environmentally informed, nongenetic dysfunction may occur, she focuses on the example of parents' histories of exposure to common agents of modern inhalational anesthesia, a highly toxic exposure that in mammalian models has been seen to induce heritable neurodevelopmental abnormality in offspring born of exposed germline.

How are nervous systems remodeled in complex metazoans?

Early in development the nervous system is constructed with far too many neurons that make an excessive number of synaptic connections.  Later, a wave of neuronal remodeling radically reshapes nervous system wiring and cell numbers through the selective elimination of excess synapses, axons and dendrites, and even whole neurons.  This remodeling is widespread across the nervous system, extensive in terms of how much individual brain regions can change (e.g. in some cases 50% of neurons integrated into a brain circuit are eliminated), and thought to be essential for optimizing nervous system function.  Perturbations of neuronal remodeling are thought to underlie devastating neurodevelopmental disorders including autism spectrum disorder, schizophrenia, and epilepsy.  This seminar will discuss our efforts to use the relatively simple nervous system of Drosophila to understand the mechanistic basis by which cells, or parts of cells, are specified for removal and eliminated from the nervous system.

2nd In-Vitro 2D & 3D Neuronal Networks Summit

The event is open to everyone interested in Neuroscience, Cell Biology, Drug Discovery, Disease Modeling, and Bio/Neuroengineering! This meeting is a platform bringing scientists from all over the world together and fostering scientific exchange and collaboration.

2nd In-Vitro 2D & 3D Neuronal Networks Summit

The event is open to everyone interested in Neuroscience, Cell Biology, Drug Discovery, Disease Modeling, and Bio/Neuroengineering! This meeting is a platform bringing scientists from all over the world together and fostering scientific exchange and collaboration.

Mapping the Dynamics of the Linear and 3D Genome of Single Cells in the Developing Brain

Three intimately related dimensions of the mammalian genome—linear DNA sequence, gene transcription, and 3D genome architecture—are crucial for the development of nervous systems. Changes in the linear genome (e.g., de novo mutations), transcriptome, and 3D genome structure lead to debilitating neurodevelopmental disorders, such as autism and schizophrenia. However, current technologies and data are severely limited: (1) 3D genome structures of single brain cells have not been solved; (2) little is known about the dynamics of single-cell transcriptome and 3D genome after birth; (3) true de novo mutations are extremely difficult to distinguish from false positives (DNA damage and/or amplification errors). Here, I filled in this longstanding technological and knowledge gap. I recently developed a high-resolution method—diploid chromatin conformation capture (Dip-C)—which resolved the first 3D structure of the human genome, tackling a longstanding problem dating back to the 1880s. Using Dip-C, I obtained the first 3D genome structure of a single brain cell, and created the first transcriptome and 3D genome atlas of the mouse brain during postnatal development. I found that in adults, 3D genome “structure types” delineate all major cell types, with high correlation between chromatin A/B compartments and gene expression. During development, both transcriptome and 3D genome are extensively transformed in the first month of life. In neurons, 3D genome is rewired across scales, correlated with gene expression modules, and independent of sensory experience. Finally, I examined allele-specific structure of imprinted genes, revealing local and chromosome-wide differences. More recently, I expanded my 3D genome atlas to the human and mouse cerebellum—the most consistently affected brain region in autism. I uncovered unique 3D genome rewiring throughout life, providing a structural basis for the cerebellum’s unique mode of development and aging. In addition, to accurately measure de novo mutations in a single cell, I developed a new method—multiplex end-tagging amplification of complementary strands (META-CS), which eliminates nearly all false positives by virtue of DNA complementarity. Using META-CS, I determined the true mutation spectrum of single human brain cells, free from chemical artifacts. Together, my findings uncovered an unknown dimension of neurodevelopment, and open up opportunities for new treatments for autism and other developmental disorders.

One by one: brain organoid modelling of neurodevelopmental disorders at single cell resolution

The use of milk exosomes to increase the expression of SYNGAP1 expression in SYNGAP1 mice

An Introduction to Autism BrainNet

Diversification of cortical inhibitory circuits & Molecular programs orchestrating the wiring of inhibitory circuitries

GABAergic interneurons play crucial roles in the regulation of neural activity in the cerebral cortex. In this Dual Lecture, Prof Oscar Marín and Prof Beatriz Rico will discuss several aspects of the formation of inhibitory circuits in the mammalian cerebral cortex. Prof. Marín will provide an overview of the mechanisms regulating the generation of the remarkable diversity of GABAergic interneurons and their ultimate numbers. Prof. Rico will describe the molecular logic through which specific pyramidal cell-interneuron circuits are established in the cerebral cortex, and how alterations in some of these connectivity motifs might be liked to disease.   Our web pages for reference: https://devneuro.org.uk/marinlab/ & https://devneuro.org.uk/rico/default

Translational Biomarkers in Preclinical Models of Neurodevelopmental Disorders

Synaptic alterations in the striatum drive ASD-related behaviors in mice

Role of primary visual cortex (V1) in visual awareness: insights from blindsight

Networking—the key to success… especially in the brain

In our everyday lives, we form connections and build up social networks that allow us to function successfully as individuals and as a society. Our social networks tend to include well-connected individuals who link us to other groups of people that we might otherwise have limited access to. In addition, we are more likely to befriend individuals who a) live nearby and b) have mutual friends. Interestingly, neurons tend to do the same…until development is perturbed. Just like social networks, neuronal networks require highly connected hubs to elicit efficient communication at minimal cost (you can’t befriend everybody you meet, nor can every neuron wire with every other!). This talk will cover some of Alex’s work showing that microscopic (cellular scale) brain networks inferred from spontaneous activity show similar complex topology to that previously described in macroscopic human brain scans. The talk will also discuss what happens when neurodevelopment is disrupted in the case of a monogenic disorder called Rett Syndrome. This will include simulations of neuronal activity and the effects of manipulation of model parameters as well as what happens when we manipulate real developing networks using optogenetics. If functional development can be restored in atypical networks, this may have implications for treatment of neurodevelopmental disorders like Rett Syndrome.

Stem cell approaches to understand acquired and genetic epilepsies

The Hsieh lab focuses on the mechanisms that promote neural stem cell self-renewal and differentiation in embryonic and adult brain. Using mouse models, video-EEG monitoring, viral techniques, and imaging/electrophysiological approaches, we elucidated many of the key transcriptional/epigenetic regulators of adult neurogenesis and showed aberrant new neuron integration in adult rodent hippocampus contribute to circuit disruption and seizure development. Building on this work, I will present our recent studies describing how GABA-mediated Ca2+ activity regulates the production of aberrant adult-born granule cells. In a new direction of my laboratory, we are using human induced pluripotent stem cells and brain organoid models as approaches to understand brain development and disease. Mutations in one gene, Aristaless-related homeobox (ARX), are of considerable interest since they are known to cause a common spectrum of neurodevelopmental disorders including epilepsy, autism, and intellectual disability. We have generated cortical and subpallial organoids from patients with poly-alanine expansion mutations in ARX. To understand the nature of ARX mutations in the organoid system, we are currently performing cellular, molecular, and physiological analyses. I will present these data to gain a comprehensive picture of the effect of ARX mutations in brain development. Since we do not understand how human brain development is affected by ARX mutations that contribute to epilepsy, we believe these studies will allow us to understand the mechanism of pathogenesis of ARX mutations, which has the potential to impact the diagnosis and care of patients.

Developmental trajectories of sleep EEG in neurodevelopmental disorders: Does sex matter?

FENS Forum 2024

Functional characterization of DPYSL5 gene variants involved in neurodevelopmental disorders with brain malformations

FENS Forum 2024

Human iPSC-derived neurons to investigate subtype-specific alterations in neurodevelopmental disorders: Our progress on SSADH deficiency

FENS Forum 2024

Integrating network activity with transcriptomic profiling in hiPSCs-derived neuronal networks to understand the molecular drivers of functional heterogeneity in the context of neurodevelopmental disorders

FENS Forum 2024

Investigating the pathogenic potential of CLSTN1 variants in neurodevelopmental disorders

FENS Forum 2024

Investigating the pathogenic potential of KCNH5 variants in neurodevelopmental disorders

FENS Forum 2024

PTCHD1 modulates cytoskeleton remodeling through regulation of Rac1-PAK signaling pathway, consistent with neurodevelopmental disorders phenotype

FENS Forum 2024

Rabphilin 3A: From NMDA receptor synaptic retention to neurodevelopmental disorders

FENS Forum 2024

Role of astrocytes in visual synaptic transmission and plasticity: Implications in neurodevelopmental disorders

FENS Forum 2024

The true cost of air pollution on neurodevelopmental disorders: Postnatal PM10 exposure impairs normal development in transgenic ApoE mice

FENS Forum 2024

In vivo xenotransplantation of patient iPSC-derived neurons in MECP2 neurodevelopmental disorders

FENS Forum 2024