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Heterozygous deletion of SYNGAP enzymatic domains in rats causes selective learning, social and seizure phenotypes

D. Katsanevaki, SM. Till, I. Buller-Peralta, TC. Watson, MS. Nawaz, D. Arkell, S. Tiwari, V. Kapgal, S. Biswal, JAB. Smith, NJ. Anstey, L. Mizen, N. Perentos, MW. Jones, MA. Cousin, S. Chattarji, A. Gonzalez-Sulser, O. Hardt, ER. Wood, PC. Kind
doi: https://doi.org/10.1101/2020.10.14.339192
D. Katsanevaki
1Simons Initiative for the Developing Brain, Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh, United Kingdom EH8 9XD
2Patrick Wild Centre, University of Edinburgh, Edinburgh, United Kingdom EH8 9XD
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SM. Till
1Simons Initiative for the Developing Brain, Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh, United Kingdom EH8 9XD
2Patrick Wild Centre, University of Edinburgh, Edinburgh, United Kingdom EH8 9XD
3Centre for Brain Development and Repair, Instem, Bangalore 560065, India
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I. Buller-Peralta
1Simons Initiative for the Developing Brain, Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh, United Kingdom EH8 9XD
2Patrick Wild Centre, University of Edinburgh, Edinburgh, United Kingdom EH8 9XD
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TC. Watson
1Simons Initiative for the Developing Brain, Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh, United Kingdom EH8 9XD
2Patrick Wild Centre, University of Edinburgh, Edinburgh, United Kingdom EH8 9XD
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MS. Nawaz
1Simons Initiative for the Developing Brain, Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh, United Kingdom EH8 9XD
3Centre for Brain Development and Repair, Instem, Bangalore 560065, India
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D. Arkell
1Simons Initiative for the Developing Brain, Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh, United Kingdom EH8 9XD
2Patrick Wild Centre, University of Edinburgh, Edinburgh, United Kingdom EH8 9XD
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S. Tiwari
3Centre for Brain Development and Repair, Instem, Bangalore 560065, India
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V. Kapgal
3Centre for Brain Development and Repair, Instem, Bangalore 560065, India
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S. Biswal
3Centre for Brain Development and Repair, Instem, Bangalore 560065, India
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JAB. Smith
1Simons Initiative for the Developing Brain, Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh, United Kingdom EH8 9XD
2Patrick Wild Centre, University of Edinburgh, Edinburgh, United Kingdom EH8 9XD
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NJ. Anstey
1Simons Initiative for the Developing Brain, Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh, United Kingdom EH8 9XD
2Patrick Wild Centre, University of Edinburgh, Edinburgh, United Kingdom EH8 9XD
3Centre for Brain Development and Repair, Instem, Bangalore 560065, India
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L. Mizen
1Simons Initiative for the Developing Brain, Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh, United Kingdom EH8 9XD
2Patrick Wild Centre, University of Edinburgh, Edinburgh, United Kingdom EH8 9XD
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N. Perentos
4Department of Cognition and Neural Plasticity, Ludwig-Maximilians-Universität München, 82152 München, Germany
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MW. Jones
5School of Physiology, Pharmacology and Neuroscience, University of Bristol, Biomedical Sciences Building, University Walk, Bristol BS8 1TD, United Kingdom
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MA. Cousin
1Simons Initiative for the Developing Brain, Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh, United Kingdom EH8 9XD
2Patrick Wild Centre, University of Edinburgh, Edinburgh, United Kingdom EH8 9XD
3Centre for Brain Development and Repair, Instem, Bangalore 560065, India
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S. Chattarji
1Simons Initiative for the Developing Brain, Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh, United Kingdom EH8 9XD
2Patrick Wild Centre, University of Edinburgh, Edinburgh, United Kingdom EH8 9XD
3Centre for Brain Development and Repair, Instem, Bangalore 560065, India
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A. Gonzalez-Sulser
1Simons Initiative for the Developing Brain, Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh, United Kingdom EH8 9XD
2Patrick Wild Centre, University of Edinburgh, Edinburgh, United Kingdom EH8 9XD
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O. Hardt
1Simons Initiative for the Developing Brain, Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh, United Kingdom EH8 9XD
2Patrick Wild Centre, University of Edinburgh, Edinburgh, United Kingdom EH8 9XD
3Centre for Brain Development and Repair, Instem, Bangalore 560065, India
6Department of Psychology, McGill University, Montreal, Canada - QC H3A 1G
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ER. Wood
1Simons Initiative for the Developing Brain, Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh, United Kingdom EH8 9XD
2Patrick Wild Centre, University of Edinburgh, Edinburgh, United Kingdom EH8 9XD
3Centre for Brain Development and Repair, Instem, Bangalore 560065, India
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PC. Kind
1Simons Initiative for the Developing Brain, Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh, United Kingdom EH8 9XD
2Patrick Wild Centre, University of Edinburgh, Edinburgh, United Kingdom EH8 9XD
3Centre for Brain Development and Repair, Instem, Bangalore 560065, India
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  • For correspondence: pkind@ed.ac.uk
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Abstract

Pathogenic variants in SYNGAP1 are one of the most common genetic causes of nonsyndromic intellectual disability (ID) and are considered a risk for autism spectrum disorder (ASD). SYNGAP1 encodes a synaptic GTPase activating protein that modulates the intrinsic GTPase activity of several small G-proteins and is implicated in regulating the composition of the postsynaptic density. By targeting the deletion of exons encoding the calcium/lipid binding (C2) and GTPase activating protein (GAP) domains, we generated a novel rat model to study SYNGAP related pathophysiology. We find that rats heterozygous for the C2/GAP domain deletion (Syngap+/Δ-GAP) exhibit reduced exploration and fear extinction, altered social behaviour, and spontaneous seizures, while homozygous mutants die within days after birth. This new rat model reveals that the enzymatic domains of SYNGAP are essential for normal brain function and provide an important new model system in the study of both ID/ASD and epilepsy.

Competing Interest Statement

The authors have declared no competing interest.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted October 14, 2020.
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Heterozygous deletion of SYNGAP enzymatic domains in rats causes selective learning, social and seizure phenotypes
D. Katsanevaki, SM. Till, I. Buller-Peralta, TC. Watson, MS. Nawaz, D. Arkell, S. Tiwari, V. Kapgal, S. Biswal, JAB. Smith, NJ. Anstey, L. Mizen, N. Perentos, MW. Jones, MA. Cousin, S. Chattarji, A. Gonzalez-Sulser, O. Hardt, ER. Wood, PC. Kind
bioRxiv 2020.10.14.339192; doi: https://doi.org/10.1101/2020.10.14.339192
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Heterozygous deletion of SYNGAP enzymatic domains in rats causes selective learning, social and seizure phenotypes
D. Katsanevaki, SM. Till, I. Buller-Peralta, TC. Watson, MS. Nawaz, D. Arkell, S. Tiwari, V. Kapgal, S. Biswal, JAB. Smith, NJ. Anstey, L. Mizen, N. Perentos, MW. Jones, MA. Cousin, S. Chattarji, A. Gonzalez-Sulser, O. Hardt, ER. Wood, PC. Kind
bioRxiv 2020.10.14.339192; doi: https://doi.org/10.1101/2020.10.14.339192

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