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Proteins related to ictogenesis and seizure clustering in chronic epilepsy

ABSTRACT: Seizure clustering is a common phenomenon in epilepsy. Protein expression profiles during a seizure cluster might reflect the pathomechanism underlying ictogenesis. We performed proteomic analyses to identify proteins with a specific temporal expression pattern in cluster phases and to demonstrate their potential pathomechanistic role. Pilocarpine epilepsy model mice with confirmed cluster pattern of spontaneous recurrent seizures by long-term video-electroencpehalography were sacrificed at the onset, peak, or end of a seizure cluster or in the seizure-free period. Proteomic analysis was performed in the hippocampus and the cortex. Differentially expressed proteins (DEPs) were identified and classified according to their temporal expression pattern. Among the five hippocampal (HC)-DEP classes, HC-class 1 (66 DEPs) represented disrupted cell homeostasis due to clustered seizures, HC-class 2 (63 DEPs) cluster-onset downregulated processes, HC-class 3 (42 DEPs) cluster-onset upregulated processes, and HC-class 4 (103 DEPs) consequences of clustered seizures. Especially, DEPs in HC-class 3 were hippocampus-specific and involved in axonogenesis, synaptic vesicle assembly, and neuronal projection, indicating their pathomechanistic roles in ictogenesis. Key proteins in HC-class 3 were highly interconnected and abundantly involved in those biological processes. This study described the seizure cluster-associated spatiotemporal regulation of protein expression. HC-class 3 provides insights regarding ictogenesis-related processes.

SUBMITTER: Lee W

PROVIDER: S-EPMC8563854 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Studies have reported that the subiculum is one origin of interictal-like discharges in adult patients with temporal lobe epilepsy; however, whether the subiculum represents a site of ictogenesis for neonatal seizures remains unclear. In this study, multi-electrode recording techniques were used to record epileptiform discharges induced by low-Mg2+ or high-K+ artificial cerebrospinal fluid in neonatal mouse hippocampal slices, and the spatiotemporal dynamics of the epileptiform discharges were analyzed. The Na+-K+-2Cl- cotransporter 1 (NKCC1) blocker, bumetanide, was applied to test its effect upon epileptiform discharges in low-Mg2+ model. The effect of N-methyl-d-aspartate receptors (NMDARs) antagonist, d-AP5, upon the epileptiform discharges in high-K+ model was examined. We found that the neonatal subiculum not only relayed epileptiform discharges emanating from the hippocampus proper (HP) but also initiated epileptiform discharges (interictal- and ictal-like discharges) independently. The latency to onset of the first epileptiform discharge initiated in the subiculum was similar to that initiated in the HP. Bumetanide efficiently blocked seizures in the neonatal HP, but was less effectively in suppressing seizures initiated in the subiculum. In high-K+ model, d-AP5 was more effective in blocking seizures initiated in the subiculum than that initiated in the HP. Furthermore, Western blotting analysis showed that NKCC1 expression was lower in the subiculum than that in the HP, whereas the expression of NMDAR subunits, NR2A and NR2B, was higher in the subiculum than that in the HP. Our results revealed that the subiculum was a potential site of ictogenesis in neonatal seizures and possessed similar seizure susceptibility to the HP. GABAergic excitation resulting from NKCC1 may play a less dominant role during ictogenesis in the subiculum than that in the HP. The subicular ictogenesis may be related to the glutamatergic excitation mediated by NMDARs.

Project description:ObjectivePrevious studies suggested that patients with epilepsy might be able to forecast their own seizures. This study aimed to assess the relationships between premonitory symptoms, perceived seizure risk, and future and recent self-reported and electroencephalographically (EEG)-confirmed seizures in ambulatory patients with epilepsy in their natural home environments.MethodsLong-term e-surveys were collected from patients with and without concurrent EEG recordings. Information obtained from the e-surveys included medication adherence, sleep quality, mood, stress, perceived seizure risk, and seizure occurrences preceding the survey. EEG seizures were identified. Univariate and multivariate generalized linear mixed-effect regression models were used to estimate odds ratios (ORs) for the assessment of the relationships. Results were compared with the seizure forecasting classifiers and device forecasting literature using a mathematical formula converting OR to equivalent area under the curve (AUC).ResultsFifty-four subjects returned 10 269 e-survey entries, with four subjects acquiring concurrent EEG recordings. Univariate analysis revealed that increased stress (OR = 2.01, 95% confidence interval [CI] = 1.12-3.61, AUC = .61, p = .02) was associated with increased relative odds of future self-reported seizures. Multivariate analysis showed that previous self-reported seizures (OR = 5.37, 95% CI = 3.53-8.16, AUC = .76, p < .001) were most strongly associated with future self-reported seizures, and high perceived seizure risk (OR = 3.34, 95% CI = 1.87-5.95, AUC = .69, p < .001) remained significant when prior self-reported seizures were added to the model. No correlation with medication adherence was found. No significant association was found between e-survey responses and subsequent EEG seizures.SignificanceOur results suggest that patients may tend to self-forecast seizures that occur in sequential groupings and that low mood and increased stress may be the result of previous seizures rather than independent premonitory symptoms. Patients in the small cohort with concurrent EEG showed no ability to self-predict EEG seizures. The conversion from OR to AUC values facilitates direct comparison of performance between survey and device studies involving survey premonition and forecasting.

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Proteins related to ictogenesis and seizure clustering in chronic epilepsy

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