GluN1抗体和GluN2B抗体在精神分裂症所致认知损害中的作用及机制

Recent clinical studies showed that N-methyl-D-aspartate (NMDA) receptor antibodies, like anti-GluN1 antibody and anti-GluN2B antibody, were found in patients with schizophrenia. GluN1 antibody led to reductions in spontaneous open-field activity and impairments in pre-pulse inhibition (PPI) in mice. However, the mechanism of anti-NMDA receptor antibody in cognition impairments of schizophrenia was unclear. Anti-NMDA receptor encephalitis patients show psychotic symptoms similar to schizophrenia. Previous studies showed that GluN1 antibody of anti-NMDA receptor encephalitis patients induced reduced expression of NMDA receptor by receptor internalization and disrupted cross-talk between NMDA receptor and CaMKⅡ, which lead to glutamatergic dysregulation, synaptic plasticity impairment and cognitive impairment. We hypothesized that NMDA receptor antibodies may have a similar mechanism for cognitive impairments in schizophrenia. Our study aims to clarify the role and mechanism of GluN1 antibody and GluN2B antibody in the cognitive impairments induced by schizophrenia. We will detect the effect of NMDA receptor antibodies on expression of NMDA receptor and the effect of altered NMDA receptor expression on cognitive function in mice. We will also demonstrate the signaling pathway related to changes of NMDA receptor expression and the effect of interfering NMDA receptor and the signaling pathway on cognitive impairments in mice.

最近研究显示精神分裂症患者血清中存在N-甲基-D-天冬氨酸（NMDA）受体亚单位GluN1抗体和GluN2B抗体，GluN1抗体引起小鼠自发活动能力下降和前脉冲抑制（PPI）损害，表明GluN1抗体与认知损害相关，但其在精神分裂症认知损害中的具体作用机制尚未清楚。具有NMDA受体抗体的脑炎患者与精神分裂症患者的精神症状相似，这类患者的GluN1抗体通过内吞作用下调NMDA受体表达及扰乱NMDA受体与CaMKⅡ相互作用引起谷氨酸能神经传递异常和突触可塑性损害而诱发认知损害。我们假设NMDA受体抗体在精神分裂症中可能具有类似作用机制。本项目主要研究GluN1抗体和GluN2B抗体在精神分裂症认知损害中的作用及机制，阐明这两个抗体对NMDA受体表达影响及NMDA受体表达改变对小鼠认知功能的影响，并阐明引起NMDA受体表达改变的信号通路，以及干预NMDA受体及其信号通路对小鼠认知损害的作用。

最近研究显示精神分裂症患者血清中存在N-甲基-D-天冬氨酸（N-methyl-D-aspartate，NMDA）受体亚单位GluN1抗体，且GluN1抗体与首发精神分裂症病人的阳性症状、阴性症状和认知症状呈正相关。增加的GluN1抗体引起小鼠自发活动能力下降和前脉冲抑制（pre-pulse inhibition, PPI）损害，引起精神分裂症病人记忆损害，表明GluN1抗体与认知损害相关，但NMDA受体抗体在精神分裂症认知损害中的具体作用机制尚未清楚。具有NMDA受体抗体的脑炎患者与精神分裂症患者的精神症状相似，这类患者的GluN1抗体通过内吞作用下调NMDA受体表达及扰乱NMDA受体与CaMKⅡ相互作用引起谷氨酸能神经传递异常和突触可塑性损害而诱发认知损害。我们假设NMDA受体抗体在精神分裂症中可能具有类似作用机制。本研究应用GluN1蛋白的N末端免疫兔子，制备了特异性针对GluN1蛋白N末端的抗GluN1多克隆抗体。我们探讨GluN1抗体引起的认知损害的机制。我们检测GluN1抗体是否引起谷氨酸受体和EphB2R表达的变化，是否引起小鼠海马突触可塑性改变，是否引起精神分裂症相关症状，如PPI损害和记忆损害。我们还探讨导致这些变化的信号通路，并阐明调节分子通路是否能减轻所观察到的这些损害。.本研究发现在海马中注射GluN1抗体7天后，导致小鼠海马区域GluN1亚单位表达和磷酸化降低， EphB2R表达降低，树突棘密度降低，海马CA1区的LTP受损，PPI损伤，小鼠识别记忆下降。此外，我们发现，注射GluN1抗体7天后，CaMKIIβ、ERK1/2、CREB和NF-κB的表达和磷酸化降低。过度表达CaMKIIβ可逆转GluN1亚单位表达和磷酸化的降低、树突棘密度的降低、PPI损害和识别记忆损害。我们的研究表明下调的CaMKIIβ-ERK1/2-CREB/NF-κB信号可能介导GluN1抗体相关的认知损害。GluN1抗体诱导的NMDAR功能低下可能是导致这些损害的潜在机制。我们的发现可能为减轻精神分裂症中NMDAR抗体相关的认知损害提供了可能的策略。我们的研究也提供了额外的证据来支持NMDAR功能低下是精神分裂症认知损害的潜在机制。