Developmental biology - Brain Development|
Rare Gene Mutation Affects Brain and Memory
New research suggests precision therapies for neurodevelopmental disorders...
Researchers from the University of California, Irvine (UCI), School of Medicine, have found a rare gene mutation which alters brain development in mice. The mutation impairs memory and disrupts communication between nerve cells. But, they also found memory problems can be improved by transplanting a specific type of nerve cell back into the brain. Their findings are published in Neuron.
According to Robert Hunt PhD, assistant professor of Anatomy & Neurobiology at UCI: "Mutations in hundreds of genes have been linked to neurodevelopmental disorders, many of which have devastating behavioral consequences that cannot be managed with available treatment options. A major challenge in the field is to identify the underlying cause for each of these rare genetic disorders so that new, disease-specific therapies can be developed."
The UCI team focused on the gene CHD2, which scientists believe modifies the structure of chromatin - a coiled mix of DNA with proteins - that controls whether hundreds of genes function or not.
Normally, humans have two copies of the CHD2 gene. However, in some cases one copy is lost and can lead to developmental disorders such as intellectual disability, epilepsy or autism.
Scientists believe the CHD2 gene modifies the structure of chromatin
- a coiled mix of DNA with proteins - that controls the expression (function) of hundreds of genes. Image Credit: Research Gate
To mimic the human disorder and better understand how CHD2 is involved in brain development, Hunt and his colleagues created a mouse model that possess only one functioning copy of the CHD2 gene. Remarkably, these mice had severe memory problems and an increase in electrical oscillations in their brains — similar to conditions found in people.
A closer look at these animals' brains revealed abnormal brain circuitry affecting the way neurons communicate with each other. This included fewer inhibitory interneurons
, that would normally manage brain circuit activity. In model mice, neurons showed differences in function/expression of more than 100 other genes associated with neurodevelopmental disorders
In an embryo, many altered genes found in the mouse model are involved in critical processes like neurogenesis. But in adult model mice, genes associated with neuronal activity and synapse function were also changed — suggesting, CHD2 may play different roles in (A) early brain development as opposed to (B) adult mice.
This finding prompted Hunt's team to transplant embryonic progenitor cells — which are capable of generating inhibitory interneurons — into the brains of the model mice. The team targeted the hippocampus, a brain region critical in learning and memory, for cell transplantation.
"Inhibitory neurons regulate oscillatory rhythms that are required for memory functions. We've been developing a similar interneuron cell therapy for epilepsy, so we naturally thought of trying this approach in mice with the CHD2 mutation."
Robert F. Hunt PhD, Assistant Professor, Anatomy & Neurobiology, School of Medicine, University of California, Irvine.
In the UCI study, the transplanted inhibitory cells migrated throughout the hippocampus and generated new interneurons, in effect replacing the brain cells that were missing in the mutant mouse model created for this research. In addition to having more inhibitory nerve cells, the treated model mice showed a dramatic improvement in hippocampal-dependent memory.
"At least in principle, it should be possible to develop targeted therapies for genetic disorders like CHD2 mutation,"
Hunt said. "That would be great, because in many cases, the medications that are currently available offer no therapeutic value at all."
While the new research offers an important step toward understanding the role of CHD2 in brain development and function, more studies are needed before interneuron progenitors can be used for cell therapy in clinical settings. The Hunt lab will next work on evaluating brain wiring in mice to explore how CHD2 mutations affect different neuronal pathways.
• CHD2 is widely expressed in the embryonic and mature brain
• Gene expression is broadly altered by Chd2 +/-
• Chd2 +/- mice have deficits in neuron proliferation, synaptic function and memory
• Interneuron transplantation rescues memory problems in Chd2 +/- mice
Considerable evidence suggests loss-of-function mutations in the chromatin remodeler CHD2 contribute to a broad spectrum of human neurodevelopmental disorders. However, it is unknown how CHD2 mutations lead to impaired brain function. Here we report mice with heterozygous mutations in Chd2 exhibit deficits in neuron proliferation and a shift in neuronal excitability that included divergent changes in excitatory and inhibitory synaptic function. Further in vivo experiments show that Chd2 +/- mice displayed aberrant cortical rhythmogenesis and severe deficits in long-term memory, consistent with phenotypes observed in humans. We identified broad, age-dependent transcriptional changes in Chd2 +/- mice, including alterations in neurogenesis, synaptic transmission, and disease-related genes. Deficits in interneuron density and memory caused by Chd2 +/- were reproduced by Chd2 mutation restricted to a subset of inhibitory neurons and corrected by interneuron transplantation. Our results provide initial insight into how Chd2 haploinsufficiency leads to aberrant cortical network function and impaired memory.
Young J. Kim, Sattar Khoshkhoo MD, Jan C. Frankowski, Bingyao Zhu, Saad Abbasi PhD, Sunyoung Lee, Ye Emily Wu, Robert F. Hunt and Ye Wu PhD. The research was funded by the Lennox-Gastaut Syndrome Foundation, National Institutes of Health, UCI Center for Autism Research and Translation (CART) and UCLA QCBio Collaboratory.
About the UCI School of Medicine
Each year, the UCI School of Medicine educates more than 400 medical students, as well as about 130 doctoral and master's students on the Irvine, California campus. More than 700 residents and fellows are trained at UC Irvine Medical Center in Orange, California and at other affiliated institutions. The highly regarded medical school is accredited by the Liaison Committee on Medical Accreditation and ranks among the U.S. News & World Report's top 50 medical schools in the nation for research. Dedicated to advancing medical knowledge and clinical practice through scholarly research, physician education, and high-quality care, the school of medicine offers MD, MS, and PhD Degrees; a Master of Science in Biomedical and Translational Science (MS-BATS), combined MD/MBA, MD/MS-BATS, and MD/MPH programs; and a distinctive combined MD/master's program called the Program in Medical Education for the Latino Community (PRIME-LC). For more information, visit: som.uci.edu.
About the University of California, Irvine
Founded in 1965, UCI is the youngest member of the prestigious Association of American Universities. The campus has produced three Nobel laureates and is known for its academic achievement, premier research, innovation and anteater mascot. Led by Chancellor Howard Gillman, UCI has more than 30,000 students and offers 192 degree programs. Located in one of the world's safest and most economically vibrant communities, UCI is Orange County's second-largest employer, contributing $5 billion annually to the local economy. For more on UCI, visit http://www.uci.edu.
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Scientists believe CDH2 modifies the structure of chromatin - a coiled complex made up of DNA and proteins - which then controls the function of hundreds of other genes.