Graduate School of Chemical and Biological Sciences, The Scripps Research Institute, Jupiter, United States; Departments of Neuroscience and Molecular Medicine, The Scripps Research Institute, Jupiter, United States
Departments of Neuroscience and Molecular Medicine, The Scripps Research Institute, Jupiter, United States
Thomas K Creson
Departments of Neuroscience and Molecular Medicine, The Scripps Research Institute, Jupiter, United States
Camilo Rojas
Departments of Neuroscience and Molecular Medicine, The Scripps Research Institute, Jupiter, United States
Aliza A Le
Department of Anatomy and Neurobiology, The University of California, Irvine, United States
Julie Lauterborn
Department of Anatomy and Neurobiology, The University of California, Irvine, United States
Brent Wilkinson
Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, United States
Nicolas Hartel
Mork Family Department of Chemical Engineering and Materials Science, University of Southern California, Los Angeles, United States
Nicholas Graham
Mork Family Department of Chemical Engineering and Materials Science, University of Southern California, Los Angeles, United States
Adrian Reich
Bioinformatics and Statistics Core, The Scripps Research Institute, Jupiter, United States
Gemma Gou
Molecular Physiology of the Synapse Laboratory, Institut d'Investigació Biomèdica Sant Pau, Barcelona, Spain; Universitat Autònoma de Barcelona, Bellaterra, Spain
Molecular Physiology of the Synapse Laboratory, Institut d'Investigació Biomèdica Sant Pau, Barcelona, Spain
Marcelo Coba
Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, United States
Gary Lynch
Department of Anatomy and Neurobiology, The University of California, Irvine, United States
Courtney A Miller
Graduate School of Chemical and Biological Sciences, The Scripps Research Institute, Jupiter, United States; Departments of Neuroscience and Molecular Medicine, The Scripps Research Institute, Jupiter, United States
Graduate School of Chemical and Biological Sciences, The Scripps Research Institute, Jupiter, United States; Departments of Neuroscience and Molecular Medicine, The Scripps Research Institute, Jupiter, United States
Loss-of-function variants in SYNGAP1 cause a developmental encephalopathy defined by cognitive impairment, autistic features, and epilepsy. SYNGAP1 splicing leads to expression of distinct functional protein isoforms. Splicing imparts multiple cellular functions of SynGAP proteins through coding of distinct C-terminal motifs. However, it remains unknown how these different splice sequences function in vivo to regulate neuronal function and behavior. Reduced expression of SynGAP-α1/2 C-terminal splice variants in mice caused severe phenotypes, including reduced survival, impaired learning, and reduced seizure latency. In contrast, upregulation of α1/2 expression improved learning and increased seizure latency. Mice expressing α1-specific mutations, which disrupted SynGAP cellular functions without altering protein expression, promoted seizure, disrupted synapse plasticity, and impaired learning. These findings demonstrate that endogenous SynGAP isoforms with α1/2 spliced sequences promote cognitive function and impart seizure protection. Regulation of SynGAP-αexpression or function may be a viable therapeutic strategy to broadly improve cognitive function and mitigate seizure.
