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Re-expression of SynGAP protein in adulthood improves translatable measures of brain function and behavior.

Authors
  • Creson, Thomas K1, 2
  • Rojas, Camilo1, 2
  • Hwaun, Ernie3
  • Vaissiere, Thomas1, 2
  • Kilinc, Murat1, 2
  • Jimenez-Gomez, Andres4, 5
  • Holder, Jimmy Lloyd Jr4, 5
  • Tang, Jianrong4, 5
  • Colgin, Laura L3
  • Miller, Courtney A1, 2
  • Rumbaugh, Gavin1, 2
  • 1 Department of Neuroscience, The Scripps Research Institute, Jupiter, United States. , (United States)
  • 2 Department of Molecular Medicine, The Scripps Research Institute, Jupiter, United States. , (United States)
  • 3 Department of Neuroscience, Institute for Neuroscience, Center for Learning and Memory, University of Texas at Austin, Austin, United States. , (United States)
  • 4 Jan and Dan Duncan Neurological Research Institute, Baylor College of Medicine, Houston, United States. , (United States)
  • 5 Department of Pediatrics, Baylor College of Medicine, Houston, United States. , (United States)
Type
Published Article
Journal
eLife
Publisher
"eLife Sciences Organisation, Ltd."
Publication Date
Apr 26, 2019
Volume
8
Identifiers
DOI: 10.7554/eLife.46752
PMID: 31025938
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

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. © 2019, Creson et al.

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