CHD8

EMBARGOED UNTIL 17-APR-2023 11:00 ET The findings may provide new insights into circuit abnormalities in autism. Basel, April 17, 2023 Using a new approach for studying live embryonic mouse brains at single-cell resolution, researchers have identified an active multi-layer circuit that forms in the cortex during an unexpectedly early stage of development. Perturbing the circuit genetically led to changes similar to those seen in the brains of people with autism. The findings are reported today in Cell by a team based at the Institute of Molecular and Clinical Ophthalmology Basel. “Understanding the detailed development of cell types and circuits in the cortex can provide important insights into autism and other neurodevelopmental diseases,” says Botond Roska, Director at IOB and the paper’s corresponding author. “This is what our findings confirm.” Autism has long been associated with faulty circuits in the cortex, which is the part of the brain that governs sensory perception, cognition, and other high-order functions. Most of the cortex is composed of excitatory cells called pyramidal neurons. The IOB team wanted to study when and how these neurons assemble into the first active circuits in the cortex, but that posed a difficult challenge. Pyramidal neurons measure only a tenth of the width of a human hair, and any movement during experimental procedures might lead to inaccurate recordings of activity. To keep the neurons stable for research, the team devised a surgical solution: Embryos were secured inside of agar-filled 3D holding devices within the mother’s abdominal cavity, so that normal embryonic blood flow and temperature could be maintained. The prevailing view is that the cortex develops in an “inside out fashion”, with the deepest of its six layers appearing first. Seen this way, pyramidal neurons were thought to slowly become active as they migrate to their final locations in the cortex and form connections with each other. But during the research, "we actually detected a very different activity pattern,” says Arjun Bharioke, a systems neuroscientist in IOB’s Central Visual Circuits Group, and one of the paper’s two lead authors. Focusing specifically on pyramidal neurons that develop into layer 5 of the cortex, the team discovered a very early transient circuit that was already highly active and correlated even before the six-layer cortex had formed. This indicates that the neurons were already connected prior to their migration to form layer 5. The transient circuit initially had 2 layers: a deep layer and a superficial layer. Later, the superficial layer became silent and vanished, while the classical layer-by-layer cortical development resumed, with a third intermediate layer forming layer 5. "We also wanted to understand how this circuit changes in an autism model," says Martin Munz, an IOB developmental biologist in the Central Visual Circuits Group and the paper's other lead author. Working with knock-out mouse lines missing one or both alleles of two autism-associated genes--Chd8 and Grin2b--the team made a key finding. The absence of these genes is known to cause significant autism in children. And in homozygous and heterozygous knockout mice, the superficial layer remained active as a developmental remnant. "Throughout embryonic development, it never disappeared," Munz says. Moreover, the knockout mouse brains contained patchy areas of cortical disorganization similar to those seen in people with autism. The findings suggest that the spatial organization of pyramidal neurons is regulated by the newly-found circuit, and that "changes to embryonic circuits play a role in dysfunctions associated with neurodevelopmental disorders, including autism spectrum disorder," Bharioke says. In future research, IOB researchers will "carefully look at the superficial and deep layers of this early circuitry and independently manipulate them," Roska says. "This will be instructive for learning about the etiology of neurodevelopmental diseases." Original Publication: Pyramidal neurons form active, transient, multilayered circuits perturbed by autism-associated mutations at the inception of neocortex Martin Munz, Arjun Bharioke, Georg Kosche, Verónica Moreno-Juan, Alexandra Brignall, Tiago M. Rodrigues, Alexandra Graff-Meyer, Talia Ulmer, Stephanie Haeuselmann, Dinko Pavlinic, Nicole Ledergeber, Brigitte Gross-Scherf, Balázs Rózsa, Jacek Krol, Simone Picelli, Cameron S. Cowan, Botond Roska 2023, Cell 186The publication will be released on April 17 and will be available under the following link:https://doi.org/10.1016/j.cell.2023.03.025 About IOB At the Institute of Molecular and Clinical Ophthalmology Basel (IOB), basic researchers and clinicians work hand in hand to advance the understanding of vision and its diseases, and to develop new therapies for vision loss. IOB started its operations in 2018. The institute is constituted as a foundation, granting academic freedom to its scientists. Founding partners are the University Hospital Basel, the University of Basel and Novartis. The Canton of Basel-Stadt has granted the institute substantial financial support. www.iob.ch IOB is proud to be affiliated with the University of Basel. Follow us on Social MediaTwitter @IOB_ch YouTube IOB Basel Switzerland IOB Media Contact:clara.vuille-dit-bille@iob.ch Attachments Arjun (Left) and Martin (Right) - Lab - 1 (Press) Arjun (Left) and Martin (Right) - Lab - 2 (Press) Arjun Bharioke (Portrait) (Press) Martin (Left) and Arjun (Right) - Exterior (Press) Stable Imaging from Embryos WT vs Autism Cortex Embryonic Circuit Development Embryonic Activity Martin Munz

The findings may provide new insights into circuit abnormalities in autism. Basel, April 17, 2023 Using a new approach for studying live embryonic mouse brains at single-cell resolution, researchers have identified an active multi-layer circuit that forms in the cortex during an unexpectedly early stage of development. Perturbing the circuit genetically led to changes similar to those seen in the brains of people with autism. The findings are reported today in Cell by a team based at the Institute of Molecular and Clinical Ophthalmology Basel. “Understanding the detailed development of cell types and circuits in the cortex can provide important insights into autism and other neurodevelopmental diseases,” says Botond Roska, Director at IOB and the paper’s corresponding author. “This is what our findings confirm.” Autism has long been associated with faulty circuits in the cortex, which is the part of the brain that governs sensory perception, cognition, and other high-order functions. Most of the cortex is composed of excitatory cells called pyramidal neurons. The IOB team wanted to study when and how these neurons assemble into the first active circuits in the cortex, but that posed a difficult challenge. Pyramidal neurons measure only a tenth of the width of a human hair, and any movement during experimental procedures might lead to inaccurate recordings of activity. To keep the neurons stable for research, the team devised a surgical solution: Embryos were secured inside of agar-filled 3D holding devices within the mother’s abdominal cavity, so that normal embryonic blood flow and temperature could be maintained. The prevailing view is that the cortex develops in an “inside out fashion”, with the deepest of its six layers appearing first. Seen this way, pyramidal neurons were thought to slowly become active as they migrate to their final locations in the cortex and form connections with each other. But during the research, "we actually detected a very different activity pattern,” says Arjun Bharioke, a systems neuroscientist in IOB’s Central Visual Circuits Group, and one of the paper’s two lead authors. Focusing specifically on pyramidal neurons that develop into layer 5 of the cortex, the team discovered a very early transient circuit that was already highly active and correlated even before the six-layer cortex had formed. This indicates that the neurons were already connected prior to their migration to form layer 5. The transient circuit initially had 2 layers: a deep layer and a superficial layer. Later, the superficial layer became silent and vanished, while the classical layer-by-layer cortical development resumed, with a third intermediate layer forming layer 5. "We also wanted to understand how this circuit changes in an autism model," says Martin Munz, an IOB developmental biologist in the Central Visual Circuits Group and the paper's other lead author. Working with knock-out mouse lines missing one or both alleles of two autism-associated genes--Chd8 and Grin2b--the team made a key finding. The absence of these genes is known to cause significant autism in children. And in homozygous and heterozygous knockout mice, the superficial layer remained active as a developmental remnant. "Throughout embryonic development, it never disappeared," Munz says. Moreover, the knockout mouse brains contained patchy areas of cortical disorganization similar to those seen in people with autism. The findings suggest that the spatial organization of pyramidal neurons is regulated by the newly-found circuit, and that "changes to embryonic circuits play a role in dysfunctions associated with neurodevelopmental disorders, including autism spectrum disorder," Bharioke says. In future research, IOB researchers will "carefully look at the superficial and deep layers of this early circuitry and independently manipulate them," Roska says. "This will be instructive for learning about the etiology of neurodevelopmental diseases." Original Publication: Pyramidal neurons form active, transient, multilayered circuits perturbed by autism-associated mutations at the inception of neocortex Martin Munz, Arjun Bharioke, Georg Kosche, Verónica Moreno-Juan, Alexandra Brignall, Tiago M. Rodrigues, Alexandra Graff-Meyer, Talia Ulmer, Stephanie Haeuselmann, Dinko Pavlinic, Nicole Ledergeber, Brigitte Gross-Scherf, Balázs Rózsa, Jacek Krol, Simone Picelli, Cameron S. Cowan, Botond Roska 2023, Cell 186 The publication will be released on April 17 and will be available under the following link: About IOB At the Institute of Molecular and Clinical Ophthalmology Basel (IOB), basic researchers and clinicians work hand in hand to advance the understanding of vision and its diseases, and to develop new therapies for vision loss. IOB started its operations in 2018. The institute is constituted as a foundation, granting academic freedom to its scientists. Founding partners are the University Hospital Basel, the University of Basel and Novartis. The Canton of Basel-Stadt has granted the institute substantial financial support. IOB is proud to be affiliated with the University of Basel. Follow us on Social Media Twitter @IOB_ch YouTube IOB Basel Switzerland IOB Media Contact: clara.vuille-dit-bille@iob.ch Attachments Arjun (Left) and Martin (Right) - Lab - 1 (Press) Arjun (Left) and Martin (Right) - Lab - 2 (Press) Arjun Bharioke (Portrait) (Press) Martin (Left) and Arjun (Right) - Exterior (Press) Stable Imaging from Embryos WT vs Autism Cortex Embryonic Circuit Development Embryonic Activity Martin Munz Arjun (Left) and Martin (Right) - Lab - 1 (Press) Arjun Bharioke (left) and Martin Munz (right) Arjun (Left) and Martin (Right) - Lab - 2 (Press) Arjun Bharioke (left) and Martin Munz (right) Arjun Bharioke (Portrait) (Press) Arjun Bharioke Martin (Left) and Arjun (Right) - Exterior (Press) Martin (Left) and Arjun (Right) - Exterior (Press) Stable Imaging from Embryos Method of stably recording from embryos while maintaining their health and temperature WT vs Autism Cortex Layer 5 pyramidal neurons in normal mice (left) compared with mice with autism gene knocked-out (right), showing a patch of disorganized cortex. Embryonic Circuit Development Diagrammatic represenation of embryonic circuit development, showing the new, early embryonic circuit, compared to the later formation of layer 5. Embryonic Activity Activity (red color) in a pyramidal neuron from an embryonic mouse. Example recordings from different parts of the neuron. Martin Munz Martin Munz

In adult mice with loss of CHD8 gene function, FDA-approved drug partially restores disrupted brain cell production CINCINNATI, Sept. 23, 2022 /PRNewswire/ -- Research led by a scientist at Cincinnati Children's who primarily studies brain tumors may open doors for improved treatment of autism. Autism spectrum disorder (ASD) affects about one in 40 children between ages 3 and 17, according to the National Survey of Children's Health. Those affected often experience difficulty socializing, impaired language development, repetitive behaviors, and other symptoms. Of those tested for various genes linked to the condition, nearly everyone with disruptive mutations of the gene CHD8 has autism. Continue Reading Mice with Chd8 deletion in cortical neural stem cells exhibit abnormal behaviors. This “open field test” tracked how mice moved about in an open area. The mice lacking CHD8 spent much more time hugging the perimeters. Now a study led by Qing Richard Lu, PhD, Beatrice C. Lampkin Endowed Chair in Cancer Epigenetics and Scientific Director of the Brain Tumor Center at Cincinnati Children's, sheds new light on the role CHD8 plays in brain development—both during embryonic growth and much later during adulthood. The study, published Sept. 23, 2022, in the Journal of Neuroscience, also reports that the FDA-approved antidepressant fluoxetine (marketed as Prozac) partially restores lost brain cell production, also known as neurogenesis, in mice lacking CHD8. "This is an exciting first step, but we need to further confirm these findings with more studies in a variety of mouse models," Lu says. "Longer term, it also would require large scale clinical trials before a treatment could be approved for human use." From cancer to autism Lu is a widely respected brain tumor expert who has devoted years to understanding how the brain forms and how brain development can go wrong. In previous work, his lab team became interested in how malfunctioning CHD8 genes could disrupt formation of myelin sheaths that protect and support rapid signaling between nerve cells in the brain and central nervous system. Then the team began wondering how CHD8 affects how the nerve cells themselves are formed. Among the many details in the study, the researchers found that the effects caused by disrupted CHD8 function vary considerably depending on when the disruption occurs. In mice, when CHD8 is missing from the start, brain development is deeply affected, especially in the formation of the cortex, the area that controls social behavior, thinking and problem-solving, and the hippocampus, which supports learning and memory. Many embryos with this early-stage gene deletion exhibit severe brain defects. The mice with loss of CHD8 function in the brain develop several classic autistic behaviors, including avoiding others. The effect was striking when mapping the movements of normal control mice and those that had lost CHD8 function as adults. However, the gene's function also can be disrupted at other points of development, be it during late-term pregnancy, youth, or adulthood. The team found ways to cause these disruptions in mice at different age points, then analyzed the effects. In the adult mice, CHD8 loss also impairs neurogenesis from neural precursor cells. With Prozac being one of the most widely studied antidepressants, the team already knew that the drug had been found to stimulate nerve cell growth. When they gave the drug to the mice with the CHD8 loss, they found that nerve cell production resumed. The restoration was not complete but was powerful enough that the drug merits closer study as a potential way to augment neurogenesis in CHD8-deficiency, Lu says. Next Step: More Behavior Tests Now Lu's lab is working on expanded research involving multiple lines of mice that have been developed to mimic ASD conditions. They are analyzing changes in behavior against varying doses and timepoints of treatment, and more. Three members of Lu's lab were co-first authors on this study: Chen Dong, Chuntao Zhao, and Xiang Chen. Several other colleagues from the Divisions of Development Biology and Experimental Hematology and Cancer Biology contributed. Collaborators also included scientists with Children's Hospital of Fudan University, Shanghai, China, and the University of California San Francisco. This study was funded by Cincinnati Children's Research Foundation award and a National Institutes of Health training grant (2T32CA117846-11A1). SOURCE Cincinnati Children's Hospital Medical Center