癫痫患者共病精神障碍的发生率高达普通人群的3倍，显著增加疾病负担。本课题组建立癫痫共病精神障碍病例库，报告临床特点，发现编码神经元突触前膜轴突蛋白Neurexin1的NRXN1基因突变在共病人群中高达12.5%。我们将探讨NRXN1基因突变是否癫痫共病精神障碍相关，并探讨其致病机制。本项目拟扩大样本量筛查NRXN1基因突变，探讨NRXN1基因突变相关的癫痫共病精神障碍表型与基因型的关系；选取前期研究发现的突变点T102R对HEK293细胞株进行转染，检测该突变对神经元突触成熟性、突触前区Neurexin1及其上游调节蛋白、突触后靶点蛋白neuroligin等的表达及功能的影响；选用敲除涵盖已发现微缺失的Nrxn1_73988小鼠检测癫痫与精神障碍的行为学表现、海马神经元突触前膜蛋白表达与电生理的改变。以左乙拉西坦干预细胞和动物模型，探讨抗癫痫药物诱导精神障碍是否与该致病基因的突变相关。

The incidence of epilepsy comorbidity with psychosis ranks three times of the general population. The disease burden increases once psychotic symptoms appear in cases with epilepsy. Our team set up the database for patients with epilepsy and psychosis. We reported a retrospective study on epilepsy comorbidity with psychotic disorders. In the study we reported the clinical manifestations of psychotic disorders in patients with epilepsy. We suggested a diagnostic frame of comorbidity psychosis with epilepsy according to the diagnostic criteria in DSM 5.0 and the diagnostic recommendation from International League against Epilepsy. In the following studies we conducted whole exon sequencing for 48 cases with epilepsy and psychosis and cascade screening for their family. We found that NRXN1 mutations were 12.5% positive in this cohort, which gene codes neuronal presynaptic axonal protein Neurexin1. The reported mutants of NRXN1 are associated with both epilepsy and psychosis/schizophrenia, but there were few reports on the mutants of NRXN1 in epilepsy comorbidity with psychotic disorders. Therefore, we propose the hypothesis that the mutants of the coding gene for neurexin1 play the key role in the mechanism of epilepsy comorbidity epilepsy and we are going to explore the mechanisms of pathophysiology. First of all, we are going to enlarge the recruitment and screen the mutation in NRXN1 gene to explore the relationship of phenotype and genotype. In this step we are going to enroll more patients during the studies and conduct the whole exon sequencing with the algorithm for copy number variants. Further bioinformatic analysis and cascade screening are going to be performed. In the second step we are going to explore the NRXN1 mutants in the pathophysiology. We chose the mutants point of NRXN1-T102R to establish the HEK293 cell model with this mutant. With the co-culture HEK293-NRXN1-T102R cell line with hypothalamic neurons we are going to test the synaptic mature level and expression of Neurexin1, CASK, Mint, synaptotagmin, vGAT and cGluT, which is the illustration for the role of the mutation in synaptogenesis. The function of the synapse is going to be examined through patch-clamp. The third step is to demonstrate the relationship of the mutant gene with the symptoms and the mechanism. We establish Nrxn1_73988 transgenic mice model, which gene will cover the reported deletions. We are going to induce status epilepticus with pilocarpine and to demonstrate the behavioral impairment, expression of Neurexin1 pathway related proteins and currents as above. The last step is to observe the effect of levetiracetam on the cell and mice models to explore whether the anti-epileptic drug can induce psychosis through the pathophysiology pathway with NRXN1 mutants. Therefore, in this study, to answer the question whether the NRXN1 mutants be important to epilepsy comorbidity psychosis, we are going to explore the relationship between the phenotype and genotype with enlarged database for whole exon sequencing and further bioinformatic analysis, to explore the pathophysiological mechanism of NRXN1 mutant with the cell line consisting the found mutants, to explore the relationship of symptoms and the pathophysiological results with the Nrxn1_73988 mice model, and to explore the contribution of anti-epileptic drug in the psychotic disorder through NRXN1 mutants with interfering of levetiracetam, which is the most reported culprit anti-epileptic drug in induced psychosis.