Endogenous Syngap1 alpha splice forms promote cognitive function and seizure protection
Por:
Kilinc M., Arora V., Creson T.K., Rojas C., Le A.A., Lauterborn J., Wilkinson B., Hartel N., Graham N., Reich A., Gou G., Araki Y., Bayés À., Coba M., Lynch G., Miller C.A., Rumbaugh G.
Publicada:
8 abr 2022
Resumen:
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-alpha 1/2 C-terminal splice variants in mice caused severe phenotypes, including reduced survival, impaired learning, and reduced seizure latency. In contrast, upregulation of alpha 1/2 expression improved learning and increased seizure latency. Mice expressing alpha 1-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 alpha 1/2 spliced sequences promote cognitive function and impart seizure protection. Regulation of SynGAP-aexpression or function may be a viable therapeutic strategy to broadly improve cognitive function and mitigate seizure.
Filiaciones:
Kilinc M.:
Graduate School of Chemical and Biological Sciences, Scripps Research Institute, Jupiter, United States
Departments of Neuroscience and Molecular Medicine, Scripps Research Institute, Jupiter, United States
Arora V.:
Departments of Neuroscience and Molecular Medicine, Scripps Research Institute, Jupiter, United States
Creson T.K.:
Departments of Neuroscience and Molecular Medicine, Scripps Research Institute, Jupiter, United States
Rojas C.:
Departments of Neuroscience and Molecular Medicine, Scripps Research Institute, Jupiter, United States
Le A.A.:
Department of Anatomy and Neurobiology, University of California, Irvine, United States
Lauterborn J.:
Department of Anatomy and Neurobiology, University of California, Irvine, United States
Wilkinson B.:
Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, United States
Hartel N.:
Mork Family Department of Chemical Engineering and Materials Science, University of Southern California, Los Angeles, United States
Graham N.:
Mork Family Department of Chemical Engineering and Materials Science, University of Southern California, Los Angeles, United States
Reich A.:
Bioinformatics and Statistics Core, Scripps Research Institute, Jupiter, United States
Gou G.:
Molecular Physiology of the Synapse Laboratory, Institut d'Investigació Biomèdica Sant Pau, Barcelona, Spain
Universitat Autònoma de Barcelona, Bellaterra, Spain
Araki Y.:
Department of Neuroscience, Johns Hopkins School of Medicine, Baltimore, United States
Bayés À.:
Molecular Physiology of the Synapse Laboratory, Institut d'Investigació Biomèdica Sant Pau, Barcelona, Spain
Coba M.:
Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, United States
Lynch G.:
Department of Anatomy and Neurobiology, University of California, Irvine, United States
Miller C.A.:
Graduate School of Chemical and Biological Sciences, Scripps Research Institute, Jupiter, United States
Departments of Neuroscience and Molecular Medicine, Scripps Research Institute, Jupiter, United States
Rumbaugh G.:
Graduate School of Chemical and Biological Sciences, Scripps Research Institute, Jupiter, United States
Departments of Neuroscience and Molecular Medicine, Scripps Research Institute, Jupiter, United States
Green Published, Green Submitted, gold, Gold, Green
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