Summary: A genetic subtype of ASD and schizophrenia has a duplicate gene that triggers hyperactivity in neural circuits, leading to social deficits and seizures. When the researchers reduced the level of the PRRT2 gene in mouse models of 16p11.2 duplication syndrome, social behaviors were restored and seizure activity decreased.
Source: Northwestern University
Northwestern Medicine scientists have identified the cause of a genetic subtype of autism and schizophrenia that results in social deficits and seizures in mice and humans.
Scientists have found that a key feature of this subtype is a duplicated gene that results in overactive or overexcited brain circuits. The subtype is called 16p11.2 duplication syndrome.
“We found that mice with the same genetic changes seen in humans are more likely to have seizures and also social deficits,” said lead author Marc Forrest, assistant professor of neuroscience research at Northwestern University Feinberg School of Medicine.
Study lead author Peter Penzes and his team also showed that by reducing levels of a gene – PRRT2 – in the duplicated region, brain activity in mice returned to normal, social behavior normal was restored and the seizures decreased.
“Our data therefore demonstrates that brain overactivation could underlie both seizures and social deficits in this syndrome, and that too much PRRT2 is responsible,” Forrest said.
The study has just been published in Nature Communication and was conducted in the lab of Penzes, director of the Center for Autism and Neurodevelopment and Ruth and Evelyn Dunbar Professor of Psychiatry and Behavioral Sciences at Northwestern.
Because the PRRT2 gene regulates how neurons talk to each other, inhibiting synapses, or connection points between neurons, could help treat both seizures and autism symptoms in this syndrome, Forrest said. . This approach could also be used more widely in other types of neurodevelopmental disorders with cerebral overactivation, which has been demonstrated in other subtypes.
“Our work now shows that we can focus our efforts on targeting the PRRT2 pathway for new therapies, and these could potentially cure the core symptoms of 16p11.2 duplication syndrome,” Forrest said. “If we learn how the 16p11.2 duplication causes disease, we may also be able to learn more about the causes of autism and schizophrenia, in general, and create better treatments.”
Neurodevelopmental disorders affect 10 million people in the United States
Neurodevelopmental disorders such as intellectual disability, autism, and schizophrenia are common and affect approximately 3%, or about 10 million people in the United States, but no effective treatment is available. 16p11.2 duplication syndrome affects about 0.3% of these people, or about 30,000 people in the United States.
“We don’t have a clear understanding of what causes neurodevelopmental disorders, so it’s hard to design good treatments,” Forrest said.
Different changes in DNA sequence can cause neurodevelopmental disorders
Genetic studies over the past decade have taught scientists that many different changes in DNA sequence can cause neurodevelopmental disorders. An example is copy number variants (CNVs).
CNVs are deletions or duplications of chromosomal DNA. Unlike trisomy 21 (Down syndrome), where an entire chromosome is copied, in CNVs only a small amount of genetic material is affected. In CNV, Penzes and his team studied (the 16p11.2 duplication), about 30 genes on chromosome 16 are duplicated.
Scientists are the first to study the protein changes that occur in the presence of the 16p11.2 duplication in a mouse model.
“This is important because proteins are the actual building blocks of the brain and neural circuits and offer unique insights into mRNA expression, which researchers have looked at previously,” Forrest said.
This work is part of the Center for Autism and Neurodevelopment’s efforts to understand the causes of autism and its related conditions.
Northwestern co-authors include Marc Dos Santos, Nicholas H. Piguel, Vikram A. Bagchi, Leonardo E. Dionisio, Yi-Zhi Wang, Jeffrey N. Savas, Nicole A. Hawkins, Dina Simkin, Alfred L. George Jr. and Jennifer A. Kearney.
Funding: The research was supported by grants R01MH097216 from the National Institute of Mental Health and R01NS114977 from the National Institute of Neurological Disorders and Stroke, National Institutes of Health.
About this autism and genetics research news
Author: Marla Paul
Source: Northwestern University
Contact: Marla Paul – Northwestern University
Picture: Image is in public domain
Original research: Free access.
“Rescue of Neuropsychiatric Phenotypes in a Mouse Model of 16p11.2 Duplication Syndrome by Genetic Correction of an Epilepsy Network Hub” by Marc Forrest et al. Nature Communication
Rescue of Neuropsychiatric Phenotypes in a Mouse Model of 16p11.2 Duplication Syndrome by Genetic Correction of an Epilepsy Network Hub
Neuropsychiatric disorders (NPD) are frequently co-morbid with epilepsy, but the biological basis of shared risk remains poorly understood. The 16p11.2 duplication is a copy number variant that confers risk for various NPDs, including autism spectrum disorders, schizophrenia, intellectual disability, and epilepsy.
We used a mouse model of the 16p11.2 duplication (16p11.2dup/+) to uncover the molecular and circuit properties associated with this broad phenotypic spectrum, and examined genes within the locus capable of reversing the phenotype. Quantitative proteomics revealed alterations in synaptic networks and NPD risk gene products.
We identified a subnetwork associated with epilepsy that was dysregulated at 16p11.2dup/+ mice and altered in the brain tissue of individuals with NPD. Cortical circuits of 16p11.2dup/+ mice showed hypersynchronous activity and increased release of network glutamate, which increased seizure susceptibility.
Using gene co-expression and interactome analysis, we show that PRRT2 is a major hub in the epilepsy subnetwork. Remarkably, the correction Prrt2 number of copies saved aberrant circuit properties, seizure susceptibility and social deficits in 16p11.2dup/+ mouse.
We show that proteomics and network biology can identify important disease centers in multigenic disorders and reveal mechanisms relevant to the complex symptomatology of 16p11.2 duplication carriers.