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

Katsanevaki, Danai; Till, Sally M.; Buller-Peralta, Ingrid; Watson, Thomas C.; Nawaz, Mohammad; Arkell, Daisy; Tiwari, Sanchit; Kapgal, Vijayakumar; Biswal, Shyam; Smith, John A.; Anstey, Natasha; Mizen, Lindsay; Perentos, Nicholas; Jones, Martin; Cousin, Michael A.; Chattarji, Sumantra; Gonzalez-Sulser, Alfredo; Hardt, Oliver; Wood, Emma R.; Kind, P.

doi:10.1101/2020.10.14.339192

Cited by 5 publications

(18 citation statements)

References 75 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…1A, Supplementary Fig. 1) recordings when animals were in a quiet-wake state 17 . To determine whether Syngap +/ Δ-GAP animals have abnormalities in their brain state distribution, we classified all individual 5 s recording epochs from those previous recordings as NREM sleep, REM sleep or wake (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Difficulties in both initiating and maintaining sleep as well as reduced overall sleep duration have been reported in individuals with SYNGAP1 mutations 3,8,9 . In our previous work we performed 6 hr recordings EEG recordings and found that Syngap +/ Δ-GAP animals displayed absence seizures at a higher rate than controls 17 . We have further analysed these recordings, which were made during daylight hours, resulting in rats spending approximately half of the recording time asleep.…”

Section: Discussionmentioning

confidence: 97%

“…Spectral analysis was performed that identified harmonic peaks in the power spectral density. The code used for analysis is available at https://github.com/Gonzalez-Sulser-Team/SWD-Automatic-Identification 17 .…”

Section: Methodsmentioning

confidence: 99%

“…In this study we analysed data recorded from Syngap +/ Δ-GAP and Syngap +/ + , which previously allowed us to show significant differences in the incidence and duration of absence seizures 17 . For our a priori statistical power calculations for the present study we utilized alpha = 0.05.…”

Section: Methodsmentioning

confidence: 99%

“…It is a key regulator of the postsynaptic density and in synaptic development and plasticity 16 . We recently reported on a novel rat model of SYNGAP1 haploinsufficiency in which the calcium/lipid binding (C2) and GTPase activating (GAP) domains, areas thought to be critical for the normal function of SYNGAP, have been deleted 17 . Animals heterozygous for the C2/GAP domain deletion ( Syngap +/ Δ-GAP ) displayed reduced exploration and fear extinction, altered social behaviour and spontaneous absence seizures.…”

Section: Introductionmentioning

confidence: 99%

See 4 more Smart Citations

Abnormal brain state distribution and network connectivity in aSYNGAP1rat model

Buller-Peralta

Maícas-Royo

et al. 2022

Preprint

View full text Add to dashboard Cite

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.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 97%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Abnormal brain state distribution and network connectivity in aSYNGAP1rat model

Buller-Peralta

Maícas-Royo

et al. 2022

Preprint

View full text Add to dashboard Cite

show abstract

Abnormal brain state distribution and network connectivity in aSYNGAP1rat model

Buller-Peralta

Maícas-Royo

et al. 2022

Brain Communications

View full text Add to dashboard Cite

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 domains have been deleted (Syngap+/Δ-GAP) we analysed the duration and occurrence of wake, non rapid eye movement and rapid eye movement 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 non rapid eye movement bouts are reduced and there is an increase in the average duration of both wake and non rapid eye movement 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 non rapid eye movement 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 abnormalities were mostly uncorrelated to the electrophysiological correlate of absence seizures, spike and wave discharges, as was the imaginary coherence deficit. 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 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. This matched significant reduction in connectivity during spindles when averaged regional comparisons were made. These data suggest that Syngap+/Δ-GAP rats have altered brain state dynamics and EEG connectivity, which may have clinical relevance for SYNGAP1 haploinsufficiency in humans.

show abstract

Absence seizures and sleep abnormalities in a rat model ofGRIN2Bneurodevelopmental disorder

Hristova,

Fasol,

McLaughlin

et al. 2024

Preprint

View full text Add to dashboard Cite

Pathogenic mutations inGRIN2Bare an important cause of severe neurodevelopmental disorders resulting in epilepsy, autism and intellectual disability.GRIN2Bencodes the GluN2B subunit of N-methyl-D-aspartate receptors (NMDARs), which are ionotropic glutamate receptors critical for normal development of the nervous system and synaptic plasticity. Here, we characterized a novelGRIN2Bheterozygous knockout rat model with 24-hour EEG recordings. We found rats heterozygous for the deletion (Grin2b+/-) had a higher incidence of spontaneous absence seizures than wild-type rats (Grin2b+/+). Spike and wave discharges, the electrographic correlate of absences seizures, were longer in duration and displayed increased higher overall spectral power inGrin2b+/-animals than those inGrin2b+/+. Heterozygous mutant rats also had abnormal sleep-wake brain state dynamics over the circadian cycle. Specifically, we identified a reduction in total rapid eye movement sleep and, altered distributions of non-rapid eye movement sleep and wake epochs, when compared to controls. This was accompanied by an increase in overall spectral power during non-rapid eye movement sleep inGrin2b+/-. The sleep-wake phenotypes were largely uncorrelated to the incidence of spike and wave discharges. We then tested the antiseizure efficacy of ethosuximide, a T-type voltage-gated calcium channel blocker used in the treatment of absence seizures, and memantine, a noncompetitive NMDAR antagonist currently explored as a mono or adjunctive treatment option in NMDAR related neurodevelopmental disorders. Ethosuximide reduced the number and duration of spike and wave discharges, while memantine did not affect the number of spike and wave discharges but reduced their duration. These results highlight two potential therapeutic options forGRIN2Brelated epilepsy. Our data shows the new ratGRIN2Bhaploinsufficiency model exhibits clinically relevant phenotypes. As such, it could prove crucial in deciphering underlying pathological mechanisms and developing new therapeutically translatable strategies forGRIN2Bneurodevelopmental disorders.

show abstract

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

Cited by 5 publications

References 75 publications

Abnormal brain state distribution and network connectivity in aSYNGAP1rat model

Abnormal brain state distribution and network connectivity in aSYNGAP1rat model

Abnormal brain state distribution and network connectivity in aSYNGAP1rat model

Absence seizures and sleep abnormalities in a rat model ofGRIN2Bneurodevelopmental disorder

Contact Info

Product

Resources

About