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Abnormal brain state distribution and network connectivity in a SYNGAP1 rat model

Ingrid Buller-Peralta, View ORCID ProfileJorge Maicas-Royo, Zhuoen Lu, Sally M. Till, Emma R. Wood, Peter C. Kind, Javier Escudero, View ORCID ProfileAlfredo Gonzalez-Sulser
doi: https://doi.org/10.1101/2022.02.04.479013
Ingrid Buller-Peralta
1Simons Initiative for the Developing Brain, Patrick Wild Centre, Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh, United Kingdom EH8 9XD
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Jorge Maicas-Royo
1Simons Initiative for the Developing Brain, Patrick Wild Centre, Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh, United Kingdom EH8 9XD
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  • ORCID record for Jorge Maicas-Royo
Zhuoen Lu
2School of Engineering, Institute for Digital Communications, University of Edinburgh, Edinburgh, United Kingdom EH9 3JL
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Sally M. Till
1Simons Initiative for the Developing Brain, Patrick Wild Centre, Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh, United Kingdom EH8 9XD
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Emma R. Wood
1Simons Initiative for the Developing Brain, Patrick Wild Centre, Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh, United Kingdom EH8 9XD
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Peter C. Kind
1Simons Initiative for the Developing Brain, Patrick Wild Centre, Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh, United Kingdom EH8 9XD
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Javier Escudero
2School of Engineering, Institute for Digital Communications, University of Edinburgh, Edinburgh, United Kingdom EH9 3JL
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Alfredo Gonzalez-Sulser
1Simons Initiative for the Developing Brain, Patrick Wild Centre, Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh, United Kingdom EH8 9XD
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  • ORCID record for Alfredo Gonzalez-Sulser
  • For correspondence: agonzal2@ed.ac.uk
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Abstract

Mutations in the SYNGAP1 gene are one of the common predictors of neurodevelopmental disorders, commonly resulting in individuals developing autism, intellectual disability, epilepsy, and sleep deficits. EEG recordings in neurodevelopmental disorders show potential to identify clinically translatable biomarkers to both diagnose and track the progress of novel therapeutic strategies, as well as providing insight into underlying pathological mechanisms. In a rat model of SYNGAP1 haploinsufficiency in which the exons encoding the calcium/lipid binding and GTPase activating protein (GAP) domains have been deleted (Syngap+/Δ-GAP) we analysed the duration and occurrence of wake, non rapid eye movement (NREM) and rapid eye movement (REM) brain states during 6 hour multi-electrode EEG recordings. We find that although Syngap+/Δ-GAP animals spend an equivalent percent time in wake and sleep states, they have an abnormal brain state distribution as the number of wake and NREM bouts are reduced and there is an increase in the average duration of both wake and NREM epochs. We perform connectivity analysis by calculating the average imaginary coherence between electrode pairs at varying distance thresholds during these states. In group averages from pairs of electrodes at short distances from each other, a clear reduction in connectivity during NREM is present between 11.5 Hz and 29.5 Hz, a frequency range that overlaps with sleep spindles, oscillatory phenomena thought to be important for normal brain function and memory consolidation. Sleep spindles occurrence, amplitude, power and spread across multiple electrodes were not reduced in Syngap+/Δ-GAP rats, with only a small decrease in duration detected. Nonetheless, by analysing the dynamic imaginary coherence during sleep spindles, we found a reduction in high connectivity instances between short-distance electrode pairs. Finally, by comparing the dynamic imaginary coherence during sleep spindles between individual electrode pairs, we identified a group of channels over the right somatosensory, association and visual cortices that have a significant reduction in connectivity during sleep spindles in mutant animals. These data suggest that Syngap+/Δ-GAP rats have altered brain state dynamics and EEG connectivity, which may have clinical relevance for SYNGAP haploinsufficiency in humans.

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 February 06, 2022.
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Abnormal brain state distribution and network connectivity in a SYNGAP1 rat model
Ingrid Buller-Peralta, Jorge Maicas-Royo, Zhuoen Lu, Sally M. Till, Emma R. Wood, Peter C. Kind, Javier Escudero, Alfredo Gonzalez-Sulser
bioRxiv 2022.02.04.479013; doi: https://doi.org/10.1101/2022.02.04.479013
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Abnormal brain state distribution and network connectivity in a SYNGAP1 rat model
Ingrid Buller-Peralta, Jorge Maicas-Royo, Zhuoen Lu, Sally M. Till, Emma R. Wood, Peter C. Kind, Javier Escudero, Alfredo Gonzalez-Sulser
bioRxiv 2022.02.04.479013; doi: https://doi.org/10.1101/2022.02.04.479013

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