A sex difference in the response of the rodent postsynaptic density to synGAP haploinsufficiency

Mastro, Tara L.; Preza, Anthony R.; Basu, Shinjini; Chattarji, Sumantra; Till, Sally M.; Kind, Peter C.; Kennedy, Mary B

doi:10.7554/elife.52656

Cited by 15 publications

(14 citation statements)

References 29 publications

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“…Our finding that the ∆-GAP mutant protein, which maintains its PDZ binding domain, localises to synapses would appear to rule out the possibility that disruption to the scaffolding function contributes to the phenotypes observed in our animals. However, it should be noted that SYNGAP regulation of TARPs is a process that appears selectively in neurons from female rats (Mastro et al, 2020), while the majority of rats used in this study were males. Furthermore, SYNGAP has recently been demonstrated to form a homotrimer that binds PSD-95 to cause liquid phase separation of the PSD95-SYNGAP complex (Zeng et al, 2016).…”

Section: Discussionmentioning

confidence: 89%

“…Hyperactivity is a potential confounding factor in measuring performance in tasks designed to study animal cognition, including expression of defensive behaviours used in fear conditioning and other behavioural and cognitive phenotypes reported in Syngap +/mice. What is clear is that the enzymatic domain is essential for survival since homozygous deletion of the C2/GAP domains results in perinatal lethality, similar to Syngap homozygous null mice (Kim et al, 2003;Knuesel et al, 2005;Komiyama et al, 2002) and rats (Mastro et al, 2020).…”

Section: Discussionmentioning

confidence: 94%

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

Katsanevaki

Till

Buller-Peralta

et al. 2020

Preprint

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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.

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Section: Discussionmentioning

confidence: 89%

Section: Discussionmentioning

confidence: 94%

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

Katsanevaki

Till

Buller-Peralta

et al. 2020

Preprint

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“…Synaptosome and ER/Golgi fractions were prepared from individual mouse forebrains according a recently published method (Mastro et al, 2020). Briefly, forebrains of 9-month old ZQ175 HD mice were dissected from each animal, rinsed in Buffer A (0.32 M sucrose, 1 mM NaHCO 3 , 1 mM MgCl 2 , 0.5 mM CaCl 2 , 0.1 mM phenylmethylsulphonyl chloride (PMSF, Sigma Millipore, St. Louis, MO).…”

Section: Sucrose Fractionation Of Hd Brainsmentioning

confidence: 99%

“…To determine whether seeding-competent mutant HTT species accumulate in vivo, brain homogenates of 9-month old ZQ175 HD mice were centrifuged on sucrose gradients optimized to enrich for myelin, ER/Golgi and synaptosome fractions (Mastro et al, 2020) and examined for the presence of mutant HTT by SDD-AGE and WB (Figure . 6A).…”

Section: Seeding-competent Mutant Htt Species Accumulate In the Brmentioning

confidence: 99%

Sonicated fibrils of huntingtin exon-1 preferentially seed neurons and produce toxic assemblies

Chongtham

Isas²,

Pandey³

et al. 2021

Preprint

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HD is a genetically inherited neurodegenerative disorder caused by expansion of a polyglutamine (polyQ) repeats in the exon-1 of huntingtin protein (HTT). The expanded polyQ enhances the amyloidogenic propensity of HTT exon 1 (HTTex1), which forms a heterogeneous mixture of assemblies with some being neurotoxic. While predominantly intracellular, monomeric and aggregated mutant HTT species are also present in the cerebrospinal fluids of HD patients, however, their biological properties are not well understood. To explore the role of extracellular mutant HTT in aggregation and toxicity, we investigated the possible uptake and amplification of recombinant HTTex1 assemblies in cell culture models. We found seedingcompetent species in the sonicated HTTex1 fibrils, which preferentially entered human neurons and triggered the amplification of neurotoxic assemblies; astrocytes or epithelial cells were not permissive to the HTTex1 seeding. The aggregation of HTTex1 seeds in neurons depleted endogenous HTT protein with non-pathogenic polyQ repeat, activated apoptotic caspase-3 pathway and induced nuclear fragmentation. Using a panel of novel monoclonal antibodies and genetic mutation, we identified epitopes within the N-terminal 17 amino acids and proline-rich domain of HTTex1 mediating neural seeding. Synaptosome preparations from the brains of HD mice also contained similar neurotoxic seeding-competent mutant HTT species. Our findings suggest that amyloidogenic extracellular mutant HTT assemblies may selectively enter neurons, propagate and produce neurotoxic assemblies.

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“…We next evaluated the subjects 10 years of age and over ( Figure 3 and Table III) Recent work has suggested sex bias in phenotypes associated with synaptopathies, particularly in Syngap1 rodent models 12 . We evaluated our data for a sex bias by directly comparing male and female subjects with each diagnosis (SYNGAP1-ID or PMD) as well as our healthy controls.…”

Section: Recruitmentmentioning

confidence: 99%

Sleep Abnormalities in the Synaptopathies – SYNGAP1-related Intellectual Disability and Phelan-McDermid syndrome

Smith‐Hicks

McCormack

Stowe

et al. 2020

Preprint

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Neurodevelopmental disorders are frequently associated with sleep disturbances. One class of neurodevelopmental disorders, the genetic synaptopathies, is caused by mutations in genes encoding proteins found at the synapse. Mutations in these genes cause derangement of synapse development and function. We utilized a validated sleep instrument, Childrens Sleep Habits Questionnaire (CSHQ) to discover what sleep abnormalities occur in individuals with two synaptopathies Phelan-McDermid syndrome (PMD) and SYNGAP1-related Intellectual Disability (SYNGAP1-ID) when compared with healthy controls. We found both PMD and SYNGAP1-ID have significant sleep abnormalities with SYNGAP1-ID having greater severity of sleep disturbance than PMD. We found that sleep disturbances were more severe for both disorders in individuals 10 years and older compared with those less than 10 years old. Individuals with either disorder were more likely to use sleep aids than healthy controls. Furthermore, review of polysomnography studies for individuals with SYNGAP1-ID revealed significant reduction in rapid eye movement (REM) sleep content and delayed REM latency demonstrating abnormalities in sleep architecture. In conclusion, sleep disturbances are a significant phenotype in the synaptopathies PMD and SYNGAP1-ID. Improved sleep is a viable clinical endpoint for future clinical trials for these neurodevelopmental disorders.

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A sex difference in the response of the rodent postsynaptic density to synGAP haploinsufficiency

Cited by 15 publications

References 29 publications

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

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

Sonicated fibrils of huntingtin exon-1 preferentially seed neurons and produce toxic assemblies

Sleep Abnormalities in the Synaptopathies – SYNGAP1-related Intellectual Disability and Phelan-McDermid syndrome

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