It remains unclear to what extent neurodevelopmental disorder (NDD) risk genes retain functions into adulthood and how they may influence disease phenotypes. SYNGAP1 haploinsufficiency causes a severe NDD defined by autistic traits, cognitive impairment, and epilepsy. To determine if this gene retains therapeutically-relevant biological functions into adulthood, we performed a gene restoration technique in a mouse model for SYNGAP1 haploinsufficiency. Adult restoration of SynGAP protein improved behavioral and electrophysiological measures of memory and seizure. This included the elimination of interictal events that worsened during sleep. These events may be a biomarker for generalized cortical dysfunction in SYNGAP1 disorders because they also worsened during sleep in the human patient population. We conclude that SynGAP protein retains biological functions throughout adulthood and that non-developmental functions may contribute to disease phenotypes. Thus, treatments that target debilitating aspects of severe NDDs, such as medically-refractory seizures and cognitive impairment, may be effective in adult patients.
- Gavin Rumbaugh
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Animal experimentation: Animal experiments were conducted according to protocols submitted to, and approved by, Scripps Research (Protocol #15-037 and #15-038) and the Baylor College of Medicine (Protocol #AN5585) Institutional Animal Care and Use Committees.
Human subjects: The SYNGAP1 Patient Registry  (https://syngap1registry.iamrare.org) is funded through the National Organization of Rare Disorders. Collection of human subject data was reviewed and approved by Hummingbird (Study # 2016-57-SYNGAP) and Baylor College of Medicine (Study #H-30480 and #H-41411) Institutional Review Boards.The parents of patients S3-060 and S3-080, which are distinct patients from those represented in Supplemental Table 4, provided written informed consent according to a protocol approved by the Baylor College of Medicine Institutional Review Board.
- Gary L Westbrook, Vollum Institute, United States
© 2019, Creson et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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