Abstract：
Schizophrenia (SZ) is a serious, destructive neurodevelopmental disorder. Antipsychotic medications are the primary therapy approach for this illness, but it\'s important to pay attention to the adverse effects as well. Clinical studies for SZ are currently in phase ΙΙΙ for SEP-363856 (SEP-856)-a new antipsychotic that doesn\'t work on dopamine D2 receptors. However, the underlying action mechanism of SEP-856 remains unknown. This study aimed to evaluate the impact and underlying mechanisms of SEP-856 on SZ-like behavior in a perinatal MK-801 treatment combined with social isolation from the weaning to adulthood model (MK-SI). First, we created an animal model that resembles SZ that combines the perinatal MK-801 with social isolation from weaning to adulthood. Then, different classical behavioral tests were used to evaluate the antipsychotic properties of SEP-856. The levels of proinflammatory cytokines (tumor necrosis factor-α, interleukin-6, and interleukin-1β), apoptosis-related genes (Bax and Bcl-2), and synaptic plasticity-related genes (brain-derived neurotrophic factor [BDNF] and PSD-95) in the hippocampus were analyzed by quantitative real-time PCR. Hematoxylin and eosin staining were used to observe the morphology of neurons in the hippocampal DG subregions. Western blot was performed to detect the protein expression levels of BDNF, PSD-95, Bax, Bcl-2, PI3K, p-PI3K, AKT, p-AKT, GSK-3β, p-GSK-3β in the hippocampus. MK-SI neurodevelopmental disease model studies have shown that compared with sham group, MK-SI group exhibit higher levels of autonomic activity, stereotyped behaviors, withdrawal from social interactions, dysregulated sensorimotor gating, and impaired recognition and spatial memory. These findings imply that the MK-SI model can mimic symptoms similar to those of SZ. Compared with the MK-SI model, high doses of SEP-856 all significantly reduced increased activity, improved social interaction, reduced stereotyping behavior, reversed sensorimotor gating dysregulation, and improved recognition memory and spatial memory impairment in MK-SI mice. In addition, SEP-856 can reduce the release of proinflammatory factors in the MK-SI model, promote the expression of BDNF and PSD-95 in the hippocampus, correct the Bax/Bcl-2 imbalance, turn on the PI3K/AKT/GSK-3β signaling pathway, and ultimately help the MK-SI mice\'s behavioral abnormalities. SEP-856 may play an antipsychotic role in MK-SI \"dual-hit\" model-induced SZ-like behavior mice by promoting synaptic plasticity recovery, decreasing death of hippocampal neurons, lowering the production of pro-inflammatory substances in the hippocampal region, and subsequently initiating the PI3K/AKT/GSK-3β signaling cascade.
摘要：
精神分裂症（SZ）是一种严重的，破坏性神经发育障碍.抗精神病药物是这种疾病的主要治疗方法，但也要注意副作用。SZ的临床研究目前处于SEP-363856(SEP-856)-一种对多巴胺D2受体不起作用的新型抗精神病药的II期。然而,SEP-856的潜在作用机制尚不清楚.这项研究旨在评估SEP-856对围产期MK-801治疗以及从断奶到成年模型（MK-SI）的社会隔离中SZ样行为的影响和潜在机制。首先,我们创建了一个类似SZ的动物模型,该模型将围产期MK-801与从断奶到成年的社会隔离相结合.然后，不同的经典行为测验用于评估SEP-856的抗精神病药物特性.促炎细胞因子（肿瘤坏死因子-α，白细胞介素-6和白细胞介素-1β)，凋亡相关基因（Bax和Bcl-2），通过实时定量PCR分析海马中突触可塑性相关基因（脑源性神经营养因子[BDNF]和PSD-95）。采用苏木精、伊红染色观察海马DG亚区神经元形态。Westernblot检测BDNF蛋白表达水平,PSD-95,Bax,Bcl-2,PI3K,p-PI3K,AKT,p-AKT,GSK-3β,海马中的p-GSK-3β。MK-SI神经发育疾病模型研究表明,与假手术组相比,MK-SI组表现出更高水平的自主神经活动，刻板的行为，退出社交互动，感觉运动门控失调，以及受损的识别和空间记忆。这些发现暗示MK-SI模型可以模拟类似于SZ的症状。与MK-SI模型相比，高剂量的SEP-856都显著降低了活性增加，改善社交互动，减少刻板行为，反向感觉运动门控失调，并改善了MK-SI小鼠的识别记忆和空间记忆障碍。此外,SEP-856可以减少MK-SI模型中促炎因子的释放，促进海马中BDNF和PSD-95的表达，纠正Bax/Bcl-2失衡，打开PI3K/AKT/GSK-3β信号通路，并最终帮助MK-SI小鼠的行为异常。SEP-856可能通过促进突触可塑性恢复，在MK-SI“双重打击”模型诱导的SZ样行为小鼠中发挥抗精神病作用，减少海马神经元的死亡，降低海马区促炎物质的产生，并随后启动PI3K/AKT/GSK-3β信号级联。
