We aim to advance the tools and methodologies for preclinical translation studies in mouse models of intellectual disability (ID) and related disorders, such as autism spectrum disorder and epilepsy. The goal of this project is to optimize a panel of measures that predict the extent of developmental brain damage in an emerging mouse model of ID and then use this panel to test the efficacy of FDA-approved RAS/ERK inhibitors. Diagnostic exome sequencing has identified SYNGAP1/Syngap1 as one of the most commonly disrupted genes in patients with sporadic brain developmental disorders. Our studies in mice that model this monogenic brain disorder demonstrated that life-long cognitive disruptions are caused by isolated damage to developing forebrain glutamatergic neurons. Damage to these neurons disrupts a critical period (CP) of development that drives life-long cognitive and behavioral disruptions. Syngap1 encodes a neuron-specific RasGAP and pathogenic mutations leading to haploinsufficiency enhance Ras/ERK signaling in the brain. However, it is currently unknown if elevated RAS/ERK signaling within forebrain glutamatergic neurons is the primary cause of CP damage that leads to life-long cognitive disability in this mouse model. Based on our past work that identified the core neurobiological defects that underlie this genetic from of ID, we have developed a clear and testable therapeutic hypothesis: that normalizing elevated Ras/ERK signaling in neonatal Syngap1 mutants will protect the CP from damage and thus mitigate the development of persistent cognitive and behavioral disruptions. Therapeutic development in mouse models of ID is expensive, time consuming and has yielded few, if any, translational successes. One possible reason for the lack of translatability in mouse models of ID is the dearth of highly quantifiable surrogate measures of cognitive function. Thus, in order to most effectively assess the efficacy of experimental therapeutics in Syngap1 model mice, we are also proposing to validate several highly quantifiable biomarkers of CP damage. Because abnormal cognition in these mice is caused by damage to a developmental CP, these surrogate measures have the potential to be highly informative with respect to cognitive ability in Syngap1 mice. In addition, these candidate biomarkers of CP damage have a high potential for translatability to human subjects because they can be acquired easily in both mice and humans. Importantly, some of these potential biomarkers are known to give very similar signals in both mice and humans patients with similar Syngap1 loss-of-function mutations. Validation of highly sensitive and translatable biomarkers in Syngap1 mice, combined with efficacy testing of a unique therapeutic hypothesis centered on CP protection, suggests that the work outlined in this proposal could advance the tools and methodologies used to develop experiential therapeutics. These advances could increase the success rate of therapies translated from mouse ID models to corresponding patient populations.

Public Health Relevance

The success rate of translating experimental therapeutics from mouse models of ID to human patients is exceptionally low. In order to increase the success rate of translational mouse studies, improved surrogate measures of cognitive ability and brain function are desperately needed. In a novel and exciting model of ID, we are proposing to: 1) optimize a panel of highly promising surrogate measures of developmental brain damage, and 2) test the efficacy of an experimental therapeutic to protect the developing brain from damage by exploiting this panel of measures that predict cognitive function.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Winsky, Lois M
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Scripps Florida
United States
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