X-linked cellular mosaicism underlies age-dependent occurrence of seizure-like events in mouse models of CDKL5 deficiency disorder

Terzic, Barbara; Cui, Yue; Edmondson, Andrew C.; Tang, Sheng; Sarmiento, Nicolas; Zaitseva, Daria; Marsh, Eric D.; Coulter, Douglas A.; Zhou, Zhaolan

doi:10.1016/j.nbd.2020.105176

Cited by 22 publications

(30 citation statements)

References 45 publications

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“…In contrast to the pervasive epilepsy in CDD patients, the absence of an overt seizure phenotype in Cdkl5 mutant male mice could contribute to the success of phenotypic reversibility found in this study. Recently, we uncovered the presence of epileptic spasms and seizure-like behaviors in aged, heterozygous female mouse models of CDD, but not hemizygous Cdkl5 knockout males or homozygous Cdkl5 knockout females (43,44). As we expand our work into modeling the reversibility of CDDrelated phenotypes in the relevant heterozygous female population, it will be interesting to establish whether this seizure phenotype alters the extent of rescue with Cdkl5 restoration, particularly at later time points, and whether a critical time window for treatment exists.…”

Section: Discussionmentioning

confidence: 99%

Temporal manipulation of Cdkl5 reveals essential postdevelopmental functions and reversible CDKL5 deficiency disorder–related deficits

Terzic¹,

Davatolhagh²,

Ho³

et al. 2021

Journal of Clinical Investigation

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Section: Discussionmentioning

confidence: 99%

Temporal manipulation of Cdkl5 reveals essential postdevelopmental functions and reversible CDKL5 deficiency disorder–related deficits

Terzic¹,

Davatolhagh²,

Ho³

et al. 2021

Journal of Clinical Investigation

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“…First, we gently moved the mouse into the recording station of the sound‐proofed chamber colored black on all sides with the same nesting materials as their cage. We scored mouse behavioral seizure as defined by events including Racine stages 3 (forelimb clonus with lordotic posture) to 5 (generalized tonic–clonic activity with loss of postural tone and jumping), using the modified Racine scale 30,31 . These events were separately confirmed by 2 operators.…”

Section: Methodsmentioning

confidence: 99%

Non–Cell Autonomous Epileptogenesis in Focal Cortical Dysplasia

Koh

Jang

et al. 2021

Annals of Neurology

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Objective: Low-level somatic mosaicism in the brain has been shown to be a major genetic cause of intractable focal epilepsy. However, how a relatively few mutation-carrying neurons are able to induce epileptogenesis at the local network level remains poorly understood. Methods: To probe the origin of epileptogenesis, we measured the excitability of neurons with MTOR mutation and nearby nonmutated neurons recorded by whole-cell patch-clamp and array-based electrodes comparing the topographic distribution of mutation. Computational simulation is used to understand neural network-level changes based on electrophysiological properties. To examine the underlying mechanism, we measured inhibitory and excitatory synaptic inputs in mutated neurons and nearby neurons by electrophysiological and histological methods using the mouse model and postoperative human brain tissue for cortical dysplasia. To explain non-cell-autonomous hyperexcitability, an inhibitor of adenosine kinase was injected into mice to enhance adenosine signaling and to mitigate hyperactivity of nearby nonmutated neurons. Results: We generated mice with a low-level somatic mutation in MTOR presenting spontaneous seizures. The seizuretriggering hyperexcitability originated from nonmutated neurons near mutation-carrying neurons, which proved to be less excitable than nonmutated neurons. Interestingly, the net balance between excitatory and inhibitory synaptic inputs onto mutated neurons remained unchanged. Additionally, we found that inhibition of adenosine kinase, which affects adenosine metabolism and neuronal excitability, reduced the hyperexcitability of nonmutated neurons. Interpretation: This study shows that neurons carrying somatic mutations in MTOR lead to focal epileptogenesis via non-cell-autonomous hyperexcitability of nearby nonmutated neurons.

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“…At 41.5°C, the temperature of seizure onset is higher than those observed for global Scn1a +/− mice (38.5 ± 0.2°C) [86] and hippocampal Na V 1.1 deletion mice (40.3 ± 0.2°C) [74]. There are neurodevelopmental disorder genetic models where spontaneous behavioral seizures are not seen in mice while they are in humans [87][88][89]. As female 1b +/− failed to efficiently reproduce, it is possible that milder but still DSrelevant behavioral and cognitive deficits are present in heterozygous 1b deletion mice.…”

Section: Discussionmentioning

confidence: 88%

Deletion of a non-canonical regulatory sequence causes loss of Scn1a expression and epileptic phenotypes in mice

et al. 2021

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Background Genes with multiple co-active promoters appear common in brain, yet little is known about functional requirements for these potentially redundant genomic regulatory elements. SCN1A, which encodes the NaV1.1 sodium channel alpha subunit, is one such gene with two co-active promoters. Mutations in SCN1A are associated with epilepsy, including Dravet syndrome (DS). The majority of DS patients harbor coding mutations causing SCN1A haploinsufficiency; however, putative causal non-coding promoter mutations have been identified. Methods To determine the functional role of one of these potentially redundant Scn1a promoters, we focused on the non-coding Scn1a 1b regulatory region, previously described as a non-canonical alternative transcriptional start site. We generated a transgenic mouse line with deletion of the extended evolutionarily conserved 1b non-coding interval and characterized changes in gene and protein expression, and assessed seizure activity and alterations in behavior. Results Mice harboring a deletion of the 1b non-coding interval exhibited surprisingly severe reductions of Scn1a and NaV1.1 expression throughout the brain. This was accompanied by electroencephalographic and thermal-evoked seizures, and behavioral deficits. Conclusions This work contributes to functional dissection of the regulatory wiring of a major epilepsy risk gene, SCN1A. We identified the 1b region as a critical disease-relevant regulatory element and provide evidence that non-canonical and seemingly redundant promoters can have essential function.

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X-linked cellular mosaicism underlies age-dependent occurrence of seizure-like events in mouse models of CDKL5 deficiency disorder

Cited by 22 publications

References 45 publications

Temporal manipulation of Cdkl5 reveals essential postdevelopmental functions and reversible CDKL5 deficiency disorder–related deficits

Temporal manipulation of Cdkl5 reveals essential postdevelopmental functions and reversible CDKL5 deficiency disorder–related deficits

Non–Cell Autonomous Epileptogenesis in Focal Cortical Dysplasia

Deletion of a non-canonical regulatory sequence causes loss of Scn1a expression and epileptic phenotypes in mice

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