Personalizing treatment for intellectual disabilities
Scientists have produced an approach to protecting animals against a type of genetic neural error causing intellectual disability, including serious memory impairment and altered anxiety levels.
The findings from The Scripps Research Institute (TSRI), focus on treating the effects of mutations in a gene known as Syngap1. The work has been published online ahead of print in the journal Biological Psychiatry.
"Our hope is that these studies will eventually lead to a therapy specifically designed for patients with psychiatric disorders caused by damaging Syngap1 mutations. Our model shows that the early developmental period is the critical time to treat this type of genetic disorder."
Gavin Rumbaugh PhD, TSRI associate professor and leader of the study.
Damaging mutations to Syngap1gene reduce the number of its functional proteins making it one of the most common causes for sporadic intellectual disability. Syngap1 errors are associated with schizophrenia and autism spectrum disorder, and early estimates suggest these non-inherited genetic mutations account for 2 to 8 percent of intellectual disabilites.
Sporadic intellectual disability affects approximately one percent of the worldwide population, suggesting that tens of thousands of individuals with intellectual disability may carry damaging Syngap1 mutations without knowing it.
In the study researchers followed the effects of Syngap1 mutations during development, finding in the mouse there is a critical period of neuronal growth between the first and third postnatal weeks.
"We found that a certain cortical neuron can grow too quickly in early development, which then leads to premature formations of some neural circuits."
Massimilano Aceti, Research Associate, and study first author.
Researchers reasoned this process might cause permanent errors in brain connectivity which might possibly be altered by enhancing the Syngap1 protein in newborn mice. After the mice were adults, they found a subset of neurons misconnected, suggesting that errors in early growth of neurons can lead to life-long neural circuit connectivity problems.
Using advanced genetic techniques to raise Syngap1 protein levels in newborn mice, the researchers were able to protect the mice — but only when the approach was started before a critical developmental period.
As a result of these studies, Rumbaugh and his colleagues are now developing a drug-screening program to look for drug compounds that could restore levels of Syngap1 protein in defective neurons.
They hope that, as personalized medicine advances, such a therapy could ultimately be tailored to patients based on their genotype.
Genetic haploinsufficiency of SYNGAP1/Syngap1 commonly occurs in developmental brain disorders, such as intellectual disability, epilepsy, schizophrenia, and autism spectrum disorder. Thus, studying mouse models of Syngap1 haploinsufficiency may uncover pathologic developmental processes common among distinct brain disorders.
A Syngap1 haploinsufficiency model was used to explore the relationship between critical period dendritic spine abnormalities, cortical circuit assembly, and the window for genetic rescue to understand how damaging mutations disrupt key substrates of mouse brain development.
Syngap1 mutations broadly disrupted a developmentally sensitive period that corresponded to the period of heightened postnatal cortical synaptogenesis. Pathogenic Syngap1 mutations caused a coordinated acceleration of dendrite elongation and spine morphogenesis and pruning of these structures in neonatal cortical pyramidal neurons. These mutations also prevented a form of developmental structural plasticity associated with experience-dependent reorganization of brain circuits. Consistent with these findings, Syngap1 mutant mice displayed an altered pattern of long-distance synaptic inputs into a cortical area important for cognition. Interestingly, the ability to genetically improve the behavioral endophenotype of Syngap1 mice decreased slowly over postnatal development and mapped onto the developmental period of coordinated dendritic insults.
Pathogenic Syngap1 mutations have a profound impact on the dynamics and structural integrity of pyramidal cell postsynaptic structures known to guide the de novo wiring of nascent cortical circuits. These findings support the idea that disrupted critical periods of dendritic growth and spine plasticity may be a common pathologic process in developmental brain disorders.
In addition to Rumbaugh and Aceti, other authors of the study, "Syngap1 Haploinsufficiency Damages a Postnatal Critical Period of Pyramidal Cell Structural Maturation Linked to Cortical Circuit Assembly," include Thomas K. Creson, Thomas Vaissiere, Camilo Rojas, Wen-Chin Huang, Ya-Xian Wang, Ronald S. Petralia, Damon T. Page and Courtney A. Miller of TSRI. For more information, see http://www.biologicalpsychiatryjournal.com/article/S0006-3223%2814%2900593-9/abstract
This work was supported by the National Institutes of Health's National Institute for Neurological Disorders and Stroke (R01NS064079), National Institute for Mental Health (R01MH096847), National Institute for Drug Abuse (R01 DA034116; R03 DA033499) and National Institute on Deafness and Other Communication Disorders/National Institutes of Health Intramural Research Program; Mrs. Nancy Lurie; and the State of Florida.
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