Altered expression of signaling pathways regulating neuronal excitability in hippocampal tissue of temporal lobe epilepsy patients with low and high seizure frequency

Hammer, Michael F.; Sprissler, Ryan; Bina, Robert; Lau, Branden; Johnstone, Laurel; Walter, C.; Labiner, David M.; Weinand, Martin E.

doi:10.1016/j.eplepsyres.2019.05.013

Cited by 7 publications

(10 citation statements)

References 72 publications

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“…Post-TC males also show a pattern of deactivation of PPAR signaling that is shared with other epilepsy syndromes, such as human TLE [ 26 ]. PPAR signaling involves a group of nuclear receptors that control lipid and glucose metabolism and energy homeostasis [ 100 ].…”

Section: Discussionmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

“…Bulk tissue was stored in RNALater (Qiagen, Valencia, CA) at −80 degrees centigrade. The technique for analyzing hippocampal gene expression was performed as previously described [ 26 , 27 ]. Briefly, RNA was isolated from hippocampal tissue and initial QC performed.…”

Section: Methodsmentioning

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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“…Moreover, disparities in the transcript abundance of a number of genes were observed in patients with MTLE exhibiting different seizure frequencies. These findings suggest that a higher seizure frequency is associated with a greater altered signaling pathways that regulate neuronal and synaptic excitability [ 68 ]. The variations in the expression of inhibitory receptors, such as the GABARα1 subunit, among certain patients may serve as an adaptive mechanism to reduce the frequency or intensity of epilepsy [ 69 ].…”

Section: Discussionmentioning

confidence: 99%

Clinical Correlation of Altered Molecular Signatures in Epileptic Human Hippocampus and Amygdala

Modarres Mousavi,

Alipour,

Noorbakhsh

et al. 2023

Mol Neurobiol

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Widespread alterations in the expression of various genes could contribute to the pathogenesis of epilepsy. The expression levels of various genes, including major inhibitory and excitatory receptors, ion channels, cell type-specific markers, and excitatory amino acid transporters, were assessed and compared between the human epileptic hippocampus and amygdala, and findings from autopsy controls. Moreover, the potential correlation between molecular alterations in epileptic brain tissues and the clinical characteristics of patients undergoing epilepsy surgery was evaluated. Our findings revealed significant and complex changes in the expression of several key regulatory genes in both the hippocampus and amygdala of patients with intractable epilepsy. The expression changes in various genes differed considerably between the epileptic hippocampus and amygdala. Different correlation patterns were observed between changes in gene expression and clinical characteristics, depending on whether the patients were considered as a whole or were subdivided. Altered molecular signatures in different groups of epileptic patients, defined within a given category, could be viewed as diagnostic biomarkers. Distinct patterns of molecular changes that distinguish these groups from each other appear to be associated with epilepsy-specific functional consequences.

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“…In this view, the capability of classifying KASE rats on their future distinct seizure frequency based on a single non-invasive TSPO PET scan at disease onset holds great potential. For instance, future studies may focus on investigating distinct expression patterns using RNA sequencing ( Hammer et al, 2019 ) or proteomic profiling ( Keck et al, 2017 , Walker et al, 2016 ) between KASE rats with divergent seizure burden (e.g. rare SRS vs frequent SRS) at disease onset to pinpoint novel candidate targets.…”

Section: Discussionmentioning

confidence: 99%

TSPO PET upregulation predicts epileptic phenotype at disease onset independently from chronic TSPO expression in a rat model of temporal lobe epilepsy

Bertoglio

Amhaoul

Goossens

et al. 2021

NeuroImage: Clinical

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Altered expression of signaling pathways regulating neuronal excitability in hippocampal tissue of temporal lobe epilepsy patients with low and high seizure frequency

Cited by 7 publications

References 72 publications

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

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

Clinical Correlation of Altered Molecular Signatures in Epileptic Human Hippocampus and Amygdala

TSPO PET upregulation predicts epileptic phenotype at disease onset independently from chronic TSPO expression in a rat model of temporal lobe epilepsy

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