Deficiency of autism-related Scn2a gene in mice disrupts sleep patterns and circadian rhythms

Ma, Zhixiong; Eaton, Muriel; Liu, Yushuang; Zhang, Jingliang; Chen, Xiaoling; Shi, Yiqiang; Que, Zhefu; Wettschurack, Kyle; Zhang, Zaiyang; Shi, Riyi; Chen, Yueyi; Kimbrough, Adam; Lanman, Nadia A.; Schust, Leah F.; Huang, Zhuo; Yang, Yang

doi:10.1016/j.nbd.2022.105690

Cited by 20 publications

(13 citation statements)

References 90 publications

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“…60 Additionally, Glun2B is the dominant NMDAR subunit mediating extracellular signal-regulated kinase 1/2 cascade activity, which is known to regulate sleep-wake distribution and NREM sleep duration. 61 Mitogen-activated protein kinases phosphorylate core clock gene regulators [62][63][64][65][66][67] , and these pathways are affected in SYNGAP1, NLGN3, FMR1 and SCN2A deficient mice and rats [68][69][70][71] , which also present with sleep impairments. 22,70,72,73 Thus, inadequate GluN2B cellular signalling could in part contribute to the sleep alterations observed in Grin2b +/mutants.…”

Section: Discussionmentioning

confidence: 99%

“…61 Mitogen-activated protein kinases phosphorylate core clock gene regulators [62][63][64][65][66][67] , and these pathways are affected in SYNGAP1, NLGN3, FMR1 and SCN2A deficient mice and rats [68][69][70][71] , which also present with sleep impairments. 22,70,72,73 Thus, inadequate GluN2B cellular signalling could in part contribute to the sleep alterations observed in Grin2b +/mutants. Future work will need to investigate whether dysregulation in diurnal behavioural patterns is present, and whether and to what extent mitogen-activated protein kinase activity and clock gene modulation is affected by GluN2B haploinsufficiency.…”

Section: Discussionmentioning

confidence: 99%

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Absence seizures and sleep abnormalities in a rat model ofGRIN2Bneurodevelopmental disorder

Hristova,

Fasol,

McLaughlin

et al. 2024

Preprint

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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.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Absence seizures and sleep abnormalities in a rat model ofGRIN2Bneurodevelopmental disorder

Hristova,

Fasol,

McLaughlin

et al. 2024

Preprint

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“…Several epileptic driver genes have been known to affect circadian rhythms and the sleep–wake cycle. Scn1a +/ − DS mice display impaired sleep, characteristic of an extended sleep period and fragmented non-rapid eye movement (NREM) sleep [ 105 ], whereas Scn2a −/− mice result in reduced NREM sleep and increased wakefulness, accompanied by a disrupted spontaneous firing pattern in SCN and altered expression of core circadian clock genes [ 106 ]. Epileptic Kcna1 −/− mice exhibit a lengthened circadian period with an extended wake period and reduced sleep time, as well as damped oscillations of core circadian clock genes such as Clock , Bmal1 , and Per1 [ 107 ].…”

Section: Epilepsy Genesmentioning

confidence: 99%

Clocking Epilepsies: A Chronomodulated Strategy-Based Therapy for Rhythmic Seizures

Sun

Wang

2023

IJMS

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Epilepsy is a neurological disorder characterized by hypersynchronous recurrent neuronal activities and seizures, as well as loss of muscular control and sometimes awareness. Clinically, seizures have been reported to display daily variations. Conversely, circadian misalignment and circadian clock gene variants contribute to epileptic pathogenesis. Elucidation of the genetic bases of epilepsy is of great importance because the genetic variability of the patients affects the efficacies of antiepileptic drugs (AEDs). For this narrative review, we compiled 661 epilepsy-related genes from the PHGKB and OMIM databases and classified them into 3 groups: driver genes, passenger genes, and undetermined genes. We discuss the potential roles of some epilepsy driver genes based on GO and KEGG analyses, the circadian rhythmicity of human and animal epilepsies, and the mutual effects between epilepsy and sleep. We review the advantages and challenges of rodents and zebrafish as animal models for epileptic studies. Finally, we posit chronomodulated strategy-based chronotherapy for rhythmic epilepsies, integrating several lines of investigation for unraveling circadian mechanisms underpinning epileptogenesis, chronopharmacokinetic and chronopharmacodynamic examinations of AEDs, as well as mathematical/computational modeling to help develop time-of-day-specific AED dosing schedules for rhythmic epilepsy patients.

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“…Sleep disturbances are frequently reported in individuals with SCN2A- related NDD, highlighting a connection between SCN2A and circadian rhythms 51 . Regionspecific deficiency of Scn2a has been used model sleep disturbances in mice and is associated with disrupted firing of SCN neurons and changes in the expression of circadian entrainment pathway genes 52 . This suggests a possible mechanism by which changes in Scn2a function could lead to disrupted estrous cyclicity.…”

Section: Disrupted Estrous Cyclicity In Scn2a E/+ Micementioning

confidence: 99%

Evaluating the interplay between estrous cyclicity and induced seizure susceptibility inScn2a^K1422Emice

Echevarria-Cooper

Kearney

2023

Preprint

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Pathogenic variants in SCN2A are associated with a range of neurodevelopmental disorders (NDD). SCN2A-related NDD show wide phenotypic heterogeneity, suggesting that modifying factors must be considered in order to properly elucidate the mechanisms of pathogenic variants. Recently, we characterized neurological phenotypes in a mouse model of the variant SCN2A-p.K1422E. We demonstrated that heterozygous Scn2aK1422Efemale mice showed a distinct, reproducible distribution of flurothyl-induced seizure thresholds. Women with epilepsy often show a cyclical pattern of altered seizure susceptibility during specific phases of the menstrual cycle which can be attributed to fluctuations in hormones and corresponding changes in neurosteroid levels. Rodent models have been used extensively to examine the relationship between the estrous (menstrual) cycle, steroid hormones, and seizure susceptibility. However, the effects of the estrous cycle on seizure susceptibility have not been evaluated in the context of an epilepsy-associated genetic variant. To determine whether the estrous cycle affects susceptibility to flurothyl-induced seizures in Scn2aK1422Efemale mice, estrous cycle monitoring was performed in mice that had undergone ovariectomy (OVX), sham surgery, or no treatment prior to seizure induction. Removing the influence of circulating sex hormones via OVX did not affect the non-unimodal distribution of flurothyl seizure thresholds observed in Scn2aK1422Efemales. Additionally, flurothyl seizure thresholds were not associated with estrous cycle stage in mice that underwent sham surgery or were untreated. These data suggest that variation in Scn2aK1422Eflurothyl seizure threshold is not significantly influenced by the estrous cycle and, by extension, fluctuations in ovarian hormones. Interestingly, untreated Scn2aK1422Efemales showed evidence of disrupted estrous cyclicity, an effect not previously described in a genetic epilepsy model. This unexpected result highlights the importance of considering sex specific effects and the estrous cycle in support of more inclusive biomedical research.

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Deficiency of autism-related Scn2a gene in mice disrupts sleep patterns and circadian rhythms

Cited by 20 publications

References 90 publications

Absence seizures and sleep abnormalities in a rat model ofGRIN2Bneurodevelopmental disorder

Absence seizures and sleep abnormalities in a rat model ofGRIN2Bneurodevelopmental disorder

Clocking Epilepsies: A Chronomodulated Strategy-Based Therapy for Rhythmic Seizures

Evaluating the interplay between estrous cyclicity and induced seizure susceptibility inScn2a^K1422Emice

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Deficiency of autism-related Scn2a gene in mice disrupts sleep patterns and circadian rhythms

Cited by 20 publications

References 90 publications

Absence seizures and sleep abnormalities in a rat model ofGRIN2Bneurodevelopmental disorder

Absence seizures and sleep abnormalities in a rat model ofGRIN2Bneurodevelopmental disorder

Clocking Epilepsies: A Chronomodulated Strategy-Based Therapy for Rhythmic Seizures

Evaluating the interplay between estrous cyclicity and induced seizure susceptibility inScn2aK1422Emice

Contact Info

Product

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Evaluating the interplay between estrous cyclicity and induced seizure susceptibility inScn2a^K1422Emice