Transcription factors are potential therapeutic targets in epilepsy

Sun, Qihan; Xu, Wenbo; Piao, Jingjing; Su, Jingyun; Ge, Tongtong; Cui, Ranji; Yang, Wei; Li, Bingjin

doi:10.1111/jcmm.17518

Cited by 7 publications

(5 citation statements)

References 109 publications

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“…To accomplish this, we analyzed our DE genes for enrichment of specific transcription factor binding motifs using the HOMER software. Of particular interest was the cAMP-response element binding protein (Creb), known to be activated by phosphorylation downstream of the MAPK and PKA pathways, as well as the crucial role of Creb-mediated transcriptional regulation in response to epileptogenesis ( G. Wang et al, 2020 ; Mertz et al, 2020 ; Sun et al, 2022 ). Further analysis using HOMER showed a Creb motif upstream of 29% of the genes ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Notable among these were changes in transcription factors and genes involving the MAPK pathway, neurotrophins, and calcium ion response. Previous work also implicated the MAPK pathway as a potential disease-modifying route in epilepsy ( Parrish et al, 2018 ), while transcription factors, such as Creb, are increasingly considered as targets for therapy in seizure disorders ( Sun et al, 2022 ).…”

Section: Discussionmentioning

confidence: 99%

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RNA Sequencing Demonstrates Ex Vivo Neocortical Transcriptomic Changes Induced by Epileptiform Activity in Male and Female Mice

Vaughan,

McMeekin,

Hine

et al. 2024

eNeuro

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Seizures are generally associated with epilepsy but may also be a symptom of many other neurological conditions. A hallmark of a seizure is the intensity of the local neuronal activation, which can drive large-scale gene transcription changes. Such changes in the transcriptional profile likely alter neuronal function, thereby contributing to the pathological process. Therefore, there is a strong clinical imperative to characterize how gene expression is changed by seizure activity. To this end, we developed a simplified ex vivo technique for studying seizure-induced transcriptional changes. We compared the RNA sequencing profile in mouse neocortical tissue with up to 3 hours of epileptiform activity induced by 4-aminopyridine (4AP) relative to control brain slices not exposed to the drug. We identified over 100 genes with significantly altered expression after 4AP treatment, including multiple genes involved in MAPK, TNF, and neuroinflammatory signaling pathways, all of which have been linked to epilepsy previously. Notably, the patterns in male and female brain slices were almost identical. Various immediate early genes were among those showing the largest upregulation. The set of down-regulated genes included ones that might be expected either to increase or to decrease neuronal excitability. In summary, we found the seizure-induced transcriptional profile complex, but the changes aligned well with an analysis of published epilepsy-associated genes. We discuss how simple models may provide new angles for investigating seizure-induced transcriptional changes.Significance StatementIt is well-established that strong neuronal activation results in large-scale transcriptomic changes. Understanding this process is of particular importance in epilepsy, which is characterized by paroxysmal pathological discharges. However, the complexity of in vivo activity patterns present many difficulties in interpreting the transcriptional changes. In contrast, ex vivo seizure models provide better experimental control and quantification of activity patterns with lower welfare impact. Importantly, we now show that these models also replicate the transcriptional patterns previously reported in chronic human and animal epilepsy, thus validating their use in these kinds of studies.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

RNA Sequencing Demonstrates Ex Vivo Neocortical Transcriptomic Changes Induced by Epileptiform Activity in Male and Female Mice

Vaughan,

McMeekin,

Hine

et al. 2024

eNeuro

View full text Add to dashboard Cite

show abstract

“…To accomplish this, we analyzed our DE genes for enrichment of specific transcription factor binding motifs using the HOMER software. Of particular interest was the cAMP response-element binding protein (CREB), known to be activated by phosphorylation downstream of the MAPK and PKA pathways, as well as the crucial role of CREB-mediated transcriptional regulation in response to epileptogenesis (Mertz et al, 2020; Sun et al, 2022; Wang et al, 2020). Further analysis using HOMER showed a CREB motif upstream of 29% of the genes (Figure 4C), indicative of the involvement of CREB in mediating a large proportion of our observed gene expression changes.…”

Section: Resultsmentioning

confidence: 99%

RNA sequencing demonstratesex vivoneocortical transcriptomic changes induced by epileptiform activity in male and female mice

Vaughan,

McMeekin,

Hine

et al. 2023

Preprint

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Seizures are generally associated with epilepsy but may also be a symptom of many other neurological conditions. A hallmark of a seizure is the intensity of the local neuronal activation, which can drive large-scale gene transcription changes. Such changes in the transcriptional profile are likely to alter neuronal function, thereby contributing to the pathological process. Therefore, there is a strong clinical imperative to characterie how gene expression is changed by seizure activity. To this end, we developed a simplifiedex vivotechnique for studying seizure-induced transcriptional changes. We compared the RNA sequencing profile in mouse neocortical tissue that had up to 3 hours of epileptiform activity induced by 4-aminopyridine (4AP), relative to control brain slices not exposed to the drug. We identified over 100 genes with significantly altered expression after 4AP treatment, including multiple genes involved in MAPK, TNF, and neuroinflammatory signalling pathways, all of which have been linked to epilepsy previously. Notably, the patterns in male and female brain slices were almost identical. Various immediate early genes were among those showing the largest upregulation. The set of down-regulated genes included ones that might be expected either to increase or to decrease neuronal excitability. In summary, we found the seizure-induced transcriptional profile to be complex, but the changes aligned well with an analysis of published epilepsy-associated genes. We discuss how simple models may provide new angles for investigating seizure-induced transcriptional changes.Significance StatementIt is well-established that strong neuronal activation results in large-scale transcriptomic changes. Understanding this process is of particular importance in epilepsy, which is characterized by paroxysmal pathological discharges. The complexity ofin vivoactivity patterns, however, present many difficulties for interpretation of the transcriptional changes. In contrast,ex vivoseizure models provide better experimental control and quantification of activity patterns, with lower welfare impact. Importantly, we now show that these models also replicate the transcriptional patterns previously reported in chronic human and animal epilepsy, thus validating their use in these kinds of study.

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“…Chronic persistent Na + current is expected to trigger excess glutamate release and activation of synaptic NMDAR, which has been shown to induce strong phosphorylation of CREB and promote CREB-dependent gene transcription [ 75 ]. In addition, NMDAR mediated hyperexcitability can lead to epileptiform activity and BBB disturbance early in the process of seizure development [ 73 , 76 ]. CREB-dependent transcription also may be upstream of the induction of synaptogenesis signaling [ 73 , 77 ] and myelination signaling [ 78 , 79 ], two additional activated pathways in pre-TC males.…”

Section: Discussionmentioning

confidence: 99%

Sex differences in physiological response to increased neuronal excitability in a knockin mouse model of pediatric epilepsy

Hammer,

Krzyzaniak,

Bahramnejad

et al. 2024

Clinical Science

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Epilepsy is a common neurological disease; however, few if any of the currently marketed antiseizure medications prevent or cure epilepsy. Discovery of pathological processes in the early stages of epileptogenesis has been challenging given the common use of preclinical models that induce seizures in physiologically normal animals. Moreover, despite known sex dimorphism in neurological diseases, females are rarely included in preclinical epilepsy models. We characterized sex differences in mice carrying a pathogenic knockin variant (p.N1768D) in the Scn8a gene that causes spontaneous tonic-clonic seizures (TCs) at ~3 months of age and found that heterozygous females are more resilient than males in mortality and morbidity. To investigate the cellular mechanisms that underlie female resilience, we utilized blood-brain barrier (BBB) and hippocampal transcriptomic analyses in heterozygous mice before seizure onset (pre-TC) and in mice that experienced ~20 TCs (post-TC). In the pre-TC latent phase, both sexes exhibited leaky BBB; however, patterns of gene expression were sexually dimorphic. Females exhibited enhanced oxidative phosphorylation and protein biogenesis, while males activated gliosis and CREB signaling. After seizure onset (chronic phase), females exhibited a metabolic switch to lipid metabolism, while males exhibited increased gliosis and BBB dysfunction and a strong activation of neuroinflammatory pathways. The results underscore the central role of oxidative stress and BBB permeability in the early stages of epileptogenesis, as well as sex dimorphism in response to increasing neuronal hyperexcitability. Our results also highlight the need to include both sexes in preclinical studies to effectively translate results of drug efficacy studies.

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Transcription factors are potential therapeutic targets in epilepsy

Cited by 7 publications

References 109 publications

RNA Sequencing Demonstrates Ex Vivo Neocortical Transcriptomic Changes Induced by Epileptiform Activity in Male and Female Mice

RNA Sequencing Demonstrates Ex Vivo Neocortical Transcriptomic Changes Induced by Epileptiform Activity in Male and Female Mice

RNA sequencing demonstratesex vivoneocortical transcriptomic changes induced by epileptiform activity in male and female mice

Sex differences in physiological response to increased neuronal excitability in a knockin mouse model of pediatric epilepsy

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