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Abstract Background Exposure to general anesthesia influences neuronal functions during brain development. Recently, interneurons were found to be involved in developmental neurotoxicity by anesthetic exposure. But the underlying mechanism and long-term consequences remain elusive. Methods Pregnant mice received 2.5% sevoflurane for 6-h on gestational day 14.5. Pentylenetetrazole (PTZ)-induced seizure, anxiety- and depression-like behavior tests were performed in 30- and 60-day-old male offspring. Cortical interneurons were labeled using Rosa26-EYFP/-; Nkx2.1-Cre mice. Immunofluorescence and electrophysiology were performed to determine the cortical interneuron properties. Q-PCR and in situ hybridization (ISH) were performed for the potential mechanism, and the finding was further validated by in utero electroporation (IUE). Results In this study, we found that maternal sevoflurane exposure increased epilepsy susceptibility by using pentylenetetrazole (PTZ) induced-kindling models and enhanced anxiety- and depression-like behaviors in adolescent offspring. After sevoflurane exposure, the highly ordered cortical interneuron migration was disrupted in the fetal cortex. In addition, the resting membrane potentials of fast-spiking interneurons in the sevoflurane-treated group were more hyperpolarized in adolescence accompanied by an increase in inhibitory synapses. Both q-PCR and ISH indicated that CXCL12/CXCR4 signaling pathway downregulation might be a potential mechanism under sevoflurane developmental neurotoxicity which was further confirmed by IUE and behavioral tests. Although the above effects were obvious in adolescence, they did not persist into adulthood. Conclusions Our findings demonstrate that maternal anesthesia impairs interneuron migration through the CXCL12/CXCR4 signaling pathway, and influences the interneuron properties, leading to the increased epilepsy susceptibility in adolescent offspring. Our study provides a novel perspective on the developmental neurotoxicity of the mechanistic link between maternal use of general anesthesia and increased susceptibility to epilepsy.

Background: Exposure to general anesthesia influences neuronal functions during brain development. Recently, interneurons were found to be involved in developmental neurotoxicity by anesthetic exposure. But the underlying mechanism and long-term consequences remain elusive. Methods: Pregnant mice received 2.5% sevoflurane for 6-h on gestational day 14.5. Pentylenetetrazole (PTZ)-induced seizure, anxiety- and depression-like behavior tests were performed in 30- and 60-day-old male offspring. Cortical interneurons were labeled using Rosa26-EYFP/-; Nkx2.1-Cre mice. Immunofluorescence and electrophysiology were performed to determine the cortical interneuron properties. Q-PCR and in situ hybridization (ISH) were performed for the potential mechanism, and the finding was further validated by in utero electroporation (IUE). Results: In this study, we found that maternal sevoflurane exposure increased epilepsy susceptibility by using pentylenetetrazole (PTZ) induced-kindling models and enhanced anxiety- and depression-like behaviors in adolescent offspring. After sevoflurane exposure, the highly ordered cortical interneuron migration was disrupted in the fetal cortex. In addition, the resting membrane potentials of fast-spiking interneurons in the sevoflurane-treated group were more hyperpolarized in adolescence accompanied by an increase in inhibitory synapses. Both q-PCR and ISH indicated that CXCL12/CXCR4 signaling pathway downregulation might be a potential mechanism under sevoflurane developmental neurotoxicity which was further confirmed by IUE and behavioral tests. Although the above effects were obvious in adolescence, they did not persist into adulthood. Conclusions: Our findings demonstrate that maternal anesthesia impairs interneuron migration through the CXCL12/CXCR4 signaling pathway, and influences the interneuron properties, leading to the increased epilepsy susceptibility in adolescent offspring. Our study provides a novel perspective on the developmental neurotoxicity of the mechanistic link between maternal use of general anesthesia and increased susceptibility to epilepsy. [ABSTRACT FROM AUTHOR]

Introduction: Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is a common autoimmune encephalitis, and it is associated with psychosis, dyskinesia, and seizures. Anti-NMDAR encephalitis (NMDARE) in juveniles and adults presents different clinical charactreistics. However, the pathogenesis of juvenile anti-NMDAR encephalitis remains unclear, partly because of a lack of suitable animal models. Methods: We developed amodel of juvenile anti-NMDAR encephalitis using active immunization with an amino terminal domain peptide from the GluN1 subunit (GluN1356-385) against NMDARs in 3-week-old female C57BL/6J mice. Results: Immunofluorescence staining suggested that autoantibody levels in the hippocampus increased, and HEK-293T cells staining identified the target of the autoantibodies as GluN1, suggesting that GluN1-specific immunoglobulin G was successfully induced. Behavior assessment showed that the mice suffered significant cognition impairment and sociability reduction, which is similar to what is observed in patients affected by anti-NMDAR encephalitis. The mice also exhibited impaired long-term potentiation in hippocampal CA1. Pilocarpine-induced epilepsy was more severe and had a longer duration, while no spontaneous seizures were observed. Conclusion: The juvenile mouse model for anti-NMDAR encephalitis is of great importance to investigate the pathological mechanism and therapeutic strategies for the disease, and could accelerate the study of autoimmune encephalitis. [ABSTRACT FROM AUTHOR]

Introduction: Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is a common autoimmune encephalitis, and it is associated with psychosis, dyskinesia, and seizures. Anti-NMDAR encephalitis (NMDARE) in juveniles and adults presents different clinical charactreistics. However, the pathogenesis of juvenile anti-NMDAR encephalitis remains unclear, partly because of a lack of suitable animal models., Methods: We developed a model of juvenile anti-NMDAR encephalitis using active immunization with an amino terminal domain peptide from the GluN1 subunit (GluN1 356 - 385 ) against NMDARs in 3-week-old female C57BL/6J mice., Results: Immunofluorescence staining suggested that autoantibody levels in the hippocampus increased, and HEK-293T cells staining identified the target of the autoantibodies as GluN1, suggesting that GluN1-specific immunoglobulin G was successfully induced. Behavior assessment showed that the mice suffered significant cognition impairment and sociability reduction, which is similar to what is observed in patients affected by anti-NMDAR encephalitis. The mice also exhibited impaired long-term potentiation in hippocampal CA1. Pilocarpine-induced epilepsy was more severe and had a longer duration, while no spontaneous seizures were observed., Conclusion: The juvenile mouse model for anti-NMDAR encephalitis is of great importance to investigate the pathological mechanism and therapeutic strategies for the disease, and could accelerate the study of autoimmune encephalitis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 He, Sun, Zhu, Li, Huang, Wu, Cao, Liao, Lu, Su, Lin, Ma and Zhong.)

Epilepsy treatment with antiepileptic drugs (AEDs) is usually requires for many years. Q808 is an innovative antiepileptic chemical. It exerts effective antiepileptic effect against various epilepsy models. Exploring the gene transcriptomic profile of long-term treatment of Q808 is necessary. In the present study, hippocampus RNA-sequencing was performed to reveal the transcriptome profile of rats before and after treatment of Q808 for 28 d. Results confirmed 51 differentially expressed genes (DEGs) between Q808 and healthy control groups. Gene cluster analysis showed that most upregulated DEGs linked to response to drug and nucleus, most downregulated DEGs linked to locomotory, neuronal cell body, and drug binding. Most of DEGs were enriched in the signaling transduction, substance dependence, nervous system, and neurodegenerative disease pathways. Furthermore, quantitative real-time PCR analysis confirmed that Q808 significantly increased the expression of neuroprotective genes, such as Mdk, and decreased the mRNA levels of Penk, Drd1, and Adora2a, which are highly expressed in epilepsy models. In addition, Q808 decreased the mRNA expression of Pde10A and Drd2, which are known to be closely associated with schizophrenia. Our study may provide a theoretical basis to explore the effect of Q808 on the susceptibility to epilepsy and other neurological diseases.

• The association between ATG5 gene polymorphisms and epilepsy was investigated. • The CC genotype of rs510432 in ATG5 were higher in epilepsy patients. • The CC genotype of rs510432 in ATG5 were higher in late-onset epilepsy patients. • rs548234 were associated with the susceptibility to temporal lobe epilepsy. Autophagy is a highly conserved degradative process that has been associated with a number of neurological diseases. Autophagy-related protein 5 (ATG5) is one of the key genes for the regulation of the autophagy pathway. In this study, we investigated the potential relationship between ATG5 gene polymorphisms and epilepsy in Han Chinese population. We enrolled 112 patients with epilepsy and 100 healthy controls and detected the genotypic and allelic data of 6 single nucleotide polymorphisms (SNPs) in ATG5 (rs2245214, rs510432, rs548234, rs573775, rs6568431 and rs6937876). The associations of 6 SNPs and epilepsy were evaluated. The results revealed the genotypes of overdominant of rs510432 between controls and patients showed significant differences (P overdominant = 0.003). Subgroup analysis showed a highly significant association of rs510432 with late-onset epilepsy (P overdominant = 0.006), and rs548234 were associated with the susceptibility to temporal lobe epilepsy (P codominant = 0.002, P overdominant = 0.006). Furthermore, ATG5 was not linked to either early-onset epilepsy or drug-resistant epilepsy (p > 0.0083). These results demonstrated an association of an ATG5 gene variant with epilepsy, and stronger associations with several subgroups of epilepsy were identified. Our study may provide novel evidence for the role of ATG5 in epilepsy, and contribute to our understanding of the molecular mechanisms of this chronic neurological disease. [ABSTRACT FROM AUTHOR]

Abstract: This study examined participation rates and reasons for refusal in a genetic study of human epilepsy. The study enrolled children with epilepsy and their parents, and required signing informed consent, verbalizing assent, and giving a peripheral blood sample. One hundred sixty-eight children met inclusion criteria; 137 agreed to enroll (82%), and 31 refused (18%). Sixteen of thirty-one patients (52%) who refused cited fear of phlebotomy as the reason for refusal. All patients refusing due to fear of phlebotomy did not require blood tests for clinical purposes. As fear of phlebotomy is the primary reason for study refusal, obtaining DNA samples from a buccal swab or mouthwash protocol may be an alternative for some studies, although there are limitations to these methods. Further analysis of the factors influencing decisions to decline study enrollment is warranted. These data will help in the design of future genetic studies and may increase future participation rates. [Copyright &y& Elsevier]

Abstract: Several GWAS focused on common forms of epilepsy are underway. Currently, only one locus has been published that reached genome wide statistical significance. Two other loci that also reach genome wide statistical significance have been reported as preliminary data and are awaiting publication. Several additional loci identified in these studies fall just short of statistical significance, and it is hoped that future large scale meta-analyses will confirm these early findings and identify new loci that influence common forms of human epilepsy. Next generation DNA sequencing (NGS) studies are also underway and in the future will identify rare DNA variations of large effect that also contribute to the final epilepsy phenotypes under study. Finally, these studies have the potential to identify biomarkers of antiepileptic drug (AED) response as epilepsy patient GWAS and NGS data are stratified based on AED efficacy and tolerability. This article is part of a supplemental special issue entitled Juvenile Myoclonic Epilepsy: What is it Really? [Copyright &y& Elsevier]