Qi Xu

Mapping the Spatio-Temporal Pattern of the Mammalian Target of Rapamycin (mTOR) Activation in Temporal Lobe Epilepsy

Growing evidence from rodent models of temporal lobe epilepsy (TLE) indicates that dysregulation of the mammalian target of rapamycin (mTOR) pathway is involved in seizures and epileptogenesis. However, the role of the mTOR pathway in the epileptogenic process remains poorly understood. Here, we used an animal model of TLE and sclerotic hippocampus from patients with refractory TLE to determine whether cell-type specific activation of mTOR signaling occurs during each stage of epileptogenesis. In the TLE mouse model, we found that hyperactivation of the mTOR pathway is present in distinct hippocampal subfields at three different stages after kainate-induced seizures, and occurs in neurons of the granular and pyramidal cell layers, in reactive astrocytes, and in dispersed granule cells, respectively. In agreement with the findings in TLE mice, upregulated mTOR was observed in the sclerotic hippocampus of TLE patients. All sclerotic hippocampus (nu200a=u200a13) exhibited widespread reactive astrocytes with overactivated mTOR, some of which invaded the dispersed granular layer. Moreover, two sclerotic hippocampus exhibited mTOR activation in some of the granule cells, which was accompanied by cell body hypertrophy. Taken together, our results indicate that mTOR activation is most prominent in reactive astrocytes in both an animal model of TLE and the sclerotic hippocampus from patients with drug resistant TLE.

Association Analysis of a Polymorphism of Interleukin 1β (IL-1β) Gene with Temporal Lobe Epilepsy in a Chinese Population

Summary:u2002 Purpose: Temporal lobe epilepsy with hippocampal sclerosis (TLE‐HS+) is one of the most common medically intractable epilepsies. Although the pathogenesis of HS+ still remains highly controversial, genetics may play a role as a predisposing factor. Previous evidence in a Japanese population shows that the homozygotes for allele 2 at position –511 of the interleukin (IL)‐1β gene promoter region (IL‐1β‐511*2/2) confers susceptibility to the development of HS. However, this result has not been confirmed in populations of European ancestry. Given that the discrepancy may be attributed to ethnic differences, our aim in this study was to test the validity of a previous report in another Asian population.

Notch Signaling Activation Promotes Seizure Activity in Temporal Lobe Epilepsy

Notch signaling in the nervous system is often regarded as a developmental pathway. However, recent studies have suggested that Notch is associated with neuronal discharges. Here, focusing on temporal lobe epilepsy, we found that Notch signaling was activated in the kainic acid (KA)-induced epilepsy model and in human epileptogenic tissues. Using an acute model of seizures, we showed that DAPT, an inhibitor of Notch, inhibited ictal activity. In contrast, pretreatment with exogenous Jagged1 to elevate Notch signaling before KA application had proconvulsant effects. In vivo, we demonstrated that the impacts of activated Notch signaling on seizures can in part be attributed to the regulatory role of Notch signaling on excitatory synaptic activity in CA1 pyramidal neurons. In vitro, we found that DAPT treatment impaired synaptic vesicle endocytosis in cultured hippocampal neurons. Taken together, our findings suggest a correlation between aberrant Notch signaling and epileptic seizures. Notch signaling is up-regulated in response to seizure activity, and its activation further promotes neuronal excitation of CA1 pyramidal neurons in acute seizures.

Multi-locus association study of schizophrenia susceptibility genes with a posterior probability method

Schizophrenia is a serious neuropsychiatric illness affecting about 1% of the world’s population. It is considered a complex inheritance disorder. A number of genes are involved in combination in the etiology of the disorder. Evidence implicates the altered dopaminergic transmission in schizophrenia. In the present study, in order to identify susceptibility genes for schizophrenia in dopaminergic metabolism, we analyzed 59 single nucleotide polymorphisms (SNPs) in 24 genes of the dopaminergic pathway among 82 unrelated patients with schizophrenia and 108 matched normal controls. Considering that traditional single-locus association studies ignore the multigenic nature of complex diseases and do not take into account possible interactions between susceptibility genes, we proposed a multi-locus analysis method, using the posterior probability of morbidity as a measure of absolute disease risk for a multi-locus genotype combination, and developed an algorithm based on perturbation and average to detect the susceptibility multi-locus genotype combinations, as well as to repress noise and avoid false positive results at our best. A three-locus SNP genotype combination involved in the interactions ofCOMT andALDH3B1 genes was detected to be significantly susceptible to schizophrenia.

P03-222 A weak association of the CLDN5 locus with schizophrenia in Chinese case-control samples

Background An increasing number of studies have described the relationship between velo-cardio-facial syndrome (VCFS) and schizophrenia. In a family-based study, we found that rs10314, a single nucleotide polymorphism (SNP) present in the 3-flanking region of the CLDN5 gene, was associated with schizophrenia among a Chinese population. High false positive rate is a common problem with the association study of human diseases. It is very important to replicate an initial finding with different samples and experimental designs. Methods A total of 749 patients with schizophrenia and 383 age and sex matched healthy control subjects in Chinese population were recruited. PCR-based RFLP protocol was applied to genotype rs10314 to see its disease association. Results The χ 2 goodness-of-fit test showed that the genotypic distributions of rs10314 were in Hardy-Weinberg equilibrium in both the patient group (χ 2 =1.12, P =0.289) and the control group (χ 2 =0.22, P =0.639). rs10314 was associated with schizophrenia with an odds ratio (OR) of 1.32 in the male subjects (χ 2 =5.45, P =0.02, 95% CI 1.05-1.67) but not in the female subjects (χ 2 =0.64, P =0.425, OR=1.14, 95% CI 0.83-1.57). The χ 2 test showed a genotypic association only for combined samples (χ 2 =7.80, df=2, P =0.02). SNP rs10314 is a G to C base change. Frequency of the genotypes containing the C allele was significantly higher in the patient group than in the control group. Conclusions The present work shows that the CLDN5 gene polymorphism is more likely to be involved in schizophrenic men than women, suggesting that this gene may contribute to the gender differences in schizophrenia.