It remains unclear to what extent neurodevelopmental disorder (NDD) risk genes retain functions into adulthood and how they may influence disease phenotypes.SYNGAP1haploinsufficiency 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 forSYNGAP1haploinsufficiency.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 inSYNGAP1disorders 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
- Received: March 11,2019
- Accepted: April 15,2019
- Accepted Manuscript published:April 26,2019 (version 1)
© 2019,Creson et al.
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