MBD5 regulates NMDA receptor expression and seizures by inhibiting Stat1 transcription.

Epilepsy is considered to result from an imbalance between excitation and inhibition of the central nervous system. Pathogenic mutations in the methyl-CpG binding domain protein 5 gene (MBD5) are known to cause epilepsy. However, the function and mechanism of MBD5 in epilepsy remain elusive. Here, we found that MBD5 was mainly localized in the pyramidal cells and granular cells of mouse hippocampus, and its expression was increased in the brain tissues of mouse models of epilepsy. Exogenous overexpression of MBD5 inhibited the transcription of the signal transducer and activator of transcription 1 gene (Stat1), resulting in increased expression of N-methyl-d-aspartate receptor (NMDAR) subunit 1 (GluN1), 2A (GluN2A) and 2B (GluN2B), leading to aggravation of the epileptic behaviour phenotype in mice. The epileptic behavioural phenotype was alleviated by overexpression of STAT1 which reduced the expression of NMDARs, and by the NMDAR antagonist memantine. These results indicate that MBD5 accumulation affects seizures through STAT1-mediated inhibition of NMDAR expression in mice. Collectively, our findings suggest that the MBD5-STAT1-NMDAR pathway may be a new pathway that regulates the epileptic behavioural phenotype and may represent a new treatment target.

TMT-based proteomics profile reveals changes of the entorhinal cortex in a kainic acid model of epilepsy in mice.

Experimental modeling and clinical neuroimaging of patients has shown that certain seizures are capable of causing neuronal death. Research into cell death after seizures has identified the induction of the molecular machinery of apoptosis. Temporal lobe epilepsy (TLE) is the most common type of epilepsy in adults, which is characterized by substantial pathological abnormalities in the temporal lobe, including the hippocampus and entorhinal cortex (EC). Although decades of studies have revealed numerous molecular abnormalities in the hippocampus that are linked to TLE, the biochemical mechanisms associated with TLE in EC remain unclear. In this study, we explored these early phenotypical alterations in the EC 5 days after mice were given a systemic injection of kainic acid (KA) to induce status epilepticus (KA-SE). we used the Tandem Mass Tag (TMT) combined with LC-MS/MS approach to identify distinct proteins in the EC in a mouse model of KA-SE model. According to the findings, 355 differentially abundant proteins including 199 upregulated and 156 downregulated differentially abundant proteins were discovered. The first-ranked biological process according to Gene Ontology (GO) analysis was "negative control of extrinsic apoptotic signaling". "Apoptosis" was the most significantly enriched Kyoto Encyclopaedia of Genes and Genomes (KEGG) pathway. Compared with those in control mice, BCL2L1, NTRK2 and MAPK10 abundance levels were reduced in KA mice. MAPK10 and NTRK2 act as upstream regulators to regulate BCL2L1, and BCL2L1 Inhibits cell death by blocking the voltage- dependent anion channel (VDAC) and preventing the release of the caspase activator, CYC1, from the mitochondrial membrane. However, ITPR1 was increased at the mRNA and protein levels in KA mice. Furthermore, there was no significant difference in ACTB, TUBA1A and TUBA4A levels between the two groups. Our results offer clues to help identify biomarkers for the development of pharmacological therapies targeted at epilepsy.

Autosomal dominant lateral temporal epilepsy in a family exhibiting a rare heterozygous mutation and deletion in the leucine-rich glioma inactivated 1 gene.

Autosomal dominant lateral temporal epilepsy (ADLTE) is an inherited syndrome caused by mutations in the leucine-rich glioma inactivated 1 (LGI1) gene. In a family with six ADLTE patients spanning four generations, our linkage and exome sequencing investigations revealed a rare frameshift heterozygous mutation in LGI1 (c.1494del(p.Phe498LeufsTer15)). Gene cloning methods were used to create plasmids with wild-type and mutant LGI1 alleles. Through transfection of HEK293 cells and primary neurons, they were utilized to assess the subcellular location of wild-type and mutant LGI1. Moreover, the plasmid-transfected primary neurons were analyzed for neuronal complexity and density of dendritic spines. According to our results. the mutation decreased LGI1 secretion in transfected HEK293 cells. In primary neurons, mutant LGI1 affected neuronal polarity and complexity. Our findings have broadened the phenotypic spectrum of LGI1 mutations and provided evidence regarding the pathogenicity of this mutation. In addition, we discovered new information about the role of LGI1 in the development of temporal lobe epilepsy, along with a possible link between neuronal polarity disorder and ADLTE.

GDAP2 Overexpression Affects the Development of Neurons and Dysregulates Neuronal Excitatory Synaptic Transmission.

GDAP2 is a gene highly expressed in the human brain and encodes ganglioside-induced differentiation-associated protein 2 (GDAP2). At present, little is known about the function of GDAP2. In recent years, it has been reported that mutations in the GDAP2 gene may be involved in hereditary cerebellar ataxia. In this study, we first conducted a preliminary study on the effect of GDAP2 overexpression on cultured primary hippocampal neurons in vitro. By analysing neuronal morphology, it was found that the complexity of neurons and the number of dendritic spines increased when GDAP2 was upregulated. The electrophysiological recordings showed that GDAP2 overexpression significantly increased the frequency of mEPSCs, suggesting that GDAP2 overexpression dysregulates excitatory synaptic transmission in cultured primary hippocampal neurons in vitro. On the other hand, behavioural and field-potential recordings of epileptic mouse models showed that GDAP2 overexpression was associated with increased seizure frequency. In summary, this preliminary study suggested that GDAP2 overexpression may have a certain pathogenic effect, providing a new perspective for the study of gene-related diseases such as epilepsy.

Pre- and postoperative heart rate variability and vagus nerve stimulation in patients with drug-resistant epilepsy - A meta-analysis.

OBJECTIVE: The effect of vagus nerve stimulation (VNS), an important auxiliary therapy for treating drug-resistant epilepsy (DRE), on autonomic nerve function is still controversial. Heart rate variability is a widely used indicator of autonomic nerve function. To clarify the relationship between VNS and heart rate variability (HRV), we performed a meta-analysis to systematically evaluate the effect of VNS on HRV in patients with epilepsy. METHODS: We performed a systematic review by searching the following online databases: PubMed, Web of Science, EMBASE and the Cochrane Library. The key search terms were "vagal nerve stimulation," "epilepsy" and "heart rate variability". Other features of VNS in patients with epilepsy include postoperative changes in low-frequency (LF), high-frequency (HF) and low-frequency/high-frequency (LF/HF) heart rate variability, which were used as evaluation indices, and the Newcastle-Ottawa Quality Assessment Scale and Stata 14.0 statistical software were used for literature quality evaluation and meta-analysis. RESULTS: Twelve studies published in English were obtained, and 229 patients with epilepsy who underwent VNS were ultimately included after elimination of duplicate articles and those that did not meet the inclusion criteria. Regarding LF heart rate variability, in the response subgroup, patients with DRE with VNS presented a lower value (-0.58) before surgery than after surgery, with a 95% confidence interval (CI) ranging from -1.00 to -0.15. For HF heart rate variability, patients with DRE with VNS had a lower value (-0.45) before surgery than after surgery in the response subgroup, with a 95% CI ranging from -0.74 to -0.17. No differences were found for LF/HF values or the LF and HF values of other subgroups. CONCLUSION: VNS has little effect on the balance of sympathetic and parasympathetic nerve activity and would not be expected to cause cardiovascular autonomic dysfunction in patients with DRE. For patients with DRE, VNS can control seizures and has little effect on autonomic nervous function.