Topic: neurodevelopmental disorders

A Keystone Symposium connecting genetics, functional genomics, developmental neurobiology, and industry to identify convergent mechanisms and therapeutic opportunities in neurodevelopmental disorders.

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

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 an

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,

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 an

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

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 fu

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 nov

Developmental epileptic encephalopathies are early-onset epilepsies, often refractory to therapy, with developmental delay or regression. These disorders carry poor neurodevelopmental prognosis, with long-term refractory epilepsy and persistent cognitive, behavioral and motor deficits. Mutations in the CACNA1A gene, encoding the pore-forming α1 subunit of CaV2.1 voltage-gated calcium channels, result in a spectrum of neurological disorders, including severe, early-onset epileptic encephalopathies. Recent work from the Rossignol lab helped characterize the phenotypic spectrum of CACNA1A-relate

Gestational exposure to environmental toxins, infections, and stressors are epidemiologically linked to neurodevelopmental disorders with strong male-bias, such as autism spectrum disorder. We modeled some of these prenatal risk factors in mice, by co-exposing pregnant dams to an environmental pollutant and limited-resource stress, which robustly dysregulated the maternal immune system. Male but not female offspring displayed long-lasting behavioral abnormalities and alterations in the activity of brain networks encoding social interactions, along with disruptions of gut structure and microbio

The symposium will start with A/Prof Jenny Gunnersen who will present “New insights into mechanisms of excitatory synapse development”. Then, Dr Tommas Ellender will deal with the “Embryonic neural progenitor pools and the generation of fine-scale neural circuits” and Dr Thomas Marissal will talk about “Parvalbumin interneurons: the missing link between the micro and macroscopic alterations related to neurodevelopmental disorders?"”.

The construction of cortical circuits requires the precise formation of connections between excitatory and inhibitory neurons during early development. Multiple factors, including neurotransmitters, neuronal activity, and neuronal-glial interactions, shape how these critical circuits form. Disruptions of these early processes can disrupt circuit formation, leading to epilepsy and other neurodevelopmental disorders. Here, I will describe our work into understanding how prolonged post-natal astrocyte development in the cortex creates a permissive window for glutamate signaling that provides to

The symposium will start with Prof Cooper who will present “From neural tube to neocortex: the role of adhesion in maintaining stem cell morphology and function”. Then, Dr Tsai will talk about “In the search for new genes involved in brain development and disorders”. Dr Del Pino will deal with the “Regulation of intrinsic network activity during area patterning in the cerebral cortex”, and Dr Wang will present “Modelling Neurodevelopmental Disorders in Flies”.

Brain and neuronal network development depend on a complex sequence of events, which include neurogenesis, migration, differentiation, synaptogenesis, and synaptic pruning. Perturbations to any of these processes, for example associated with ion channel gene mutations (i.e., channelopathies), can underlie neurodevelopmental disorders such as neonatal and infantile epilepsies, strongly impair psychomotor development and cause persistent deficits in cognition, motor skills, or motor control. The therapeutic options available are very limited, and prophylactic therapies for patients at an increas

We will start our talk with a short video of our research, illustrating methods (some old and new) and findings that have provided our current understanding of how visual capabilities develop in infancy and early childhood. However, our research poses some outstanding questions. We will briefly discuss three issues, which are linked by a common focus on the development of visual attentional processing: (1) How do recurrent cortical loops contribute to development? Cortical selectivity (e.g., to orientation, motion, and binocular disparity) develops in the early months of life. However,

Recent human gene discovery efforts show that gain-of-function (GOF) variants in the KCNT1gene, which encodes a Na+-activated K+ channel subunit, cause severe epilepsies and other neurodevelopmental disorders. Although the impact of these variants on the biophysical properties of the channels is well characterized, the mechanisms that link channel dysfunction to cellular and network hyperexcitability and human disease are unknown. Furthermore, precision therapies that correct channel biophysics in non-neuronal cells have had limited success in treating human disease, highlighting the need for

Unlike even the most sophisticated current forms of artificial intelligence, developing biological organisms must build their neural hardware from scratch. Furthermore they must start to evade predators and find food before this construction process is complete. I will discuss an interdisciplinary program of mathematical and experimental work which addresses some of the computational principles underlying neural development. This includes (i) how growing axons navigate to their targets by detecting and responding to molecular cues in their environment, (ii) the formation of maps in the visual

Neurodevelopmental disorders are a group of very heterogeneous diseases in which the development of the central nervous system is defective. In neurodevelopmental disorders defective brain development translates into aberrant brain function, which can manifest for example as impaired learning, motor function, or social interaction. Despites years of investigation in animal models and clinical research on neurodevelopmental disorders, there are currently no approved pharmacological treatments for core symptoms of the vast majority of them. Here, I will share some recent work (but also some appr

Plasticity shapes the brain during development, and mechanisms of plasticity continue into adulthood to enable learning and memory. Nearly all brain functions are influenced by past events, reinforcing the view that the confluence of plasticity and computation in the same circuit elements is a core component of biological intelligence. My laboratory studies plasticity in the cerebral cortex during development, and plasticity during behaviour that is manifest as cortical dynamics. I will describe how cortical plasticity is implemented by learning rules that involve not only Hebbian changes and

Malformations of the human cerebral cortex represent a major cause of developmental disabilities. To date, animal models carrying mutations of genes so far identified in human patients with brain malformations only partially recapitulate the expected phenotypes and therefore do not provide reliable models to entirely understand the molecular and cellular mechanisms responsible for these disorders. Hence, we combine the in vivo mouse model and the human brain organoids in order to better comprehend the mechanisms involved in the migration of neurons during human development and tackle the cause

The thalamic reticular nucleus (TRN), the major source of thalamic inhibition, is known to regulate thalamocortical interactions critical for sensory processing, attention and cognition. TRN dysfunction has been linked to sensory abnormality, attention deficit and sleep disturbance across multiple neurodevelopmental disorders. Currently, little is known about the organizational principles underlying its divergent functions. In this talk, I will start with an example of how dysfunction of TRN contributes to attention deficit and sleep disruption using a mouse model of Ptchd1 mutation, which in

Mutations in dozens of chromatin regulators have been implicated in neurodevelopmental disorders. One of these genes is chromodomain helicase DNA binding 2 (CHD2), encoding for a chromatin modifier with largely unknown neuronal functions. In humans, heterozygous loss of function mutations in CHD2 are associated with severe childhood-onset epilepsy, global developmental delay, intellectual disability, and autistic-like features. Here, we characterized the epileptic and behavioral phenotypes of a mouse model with Chd2 haploinsufficiency (Chd2+/m and Chd2m/m mice). Interestingly, we discovered th

Several adverse intrauterine conditions during pregnancy may increase the risk of neurodevelopmental disorders, including Autism Spectrum Disorder (ASD). Endogenous retroviruses (ERVs) have been proposed as co-factors in the pathogenesis of ASD, also potentially useful as early biomarkers of derailed neurodevelopment. Two preclinical models of ASD, the inbred BTBR T+tf/J (BTBR) mice, and mice prenatally exposed to valproic acid, showed an altered expression of several ERVs and cytokines, in embryos, blood and brain samples at different post-natal ages. The present study aimed to characterize t

While dissociated cultures of rodent neurons on microelectrode arrays (MEAs) have become a prominent method for studying neuronal network properties, establishing human neuronal cultures with mature electrophysiological features compatible with MEAs has posed a significant challenge. The aim of this study was to establish a reliable protocol for generating human-derived neuronal networks on High Density Microelectrode Arrays (HD-MEA) and to characterize their electrophysiological features for potential applications in disease modeling and therapeutic testing. Human-induced pluripotent stem cel