Mechanisms of neurotoxicity of lupus anti-NMDAR antibodies: Electrophysiology to

项目1：“狼疮抗NMDAR抗体的神经毒性机制：电生理学对行为的影响” (Huerta Pi)。 本项目的目标是检查神经精神性红斑狼疮(NPSLE)的关键症状是否 由结合N-甲基-o-天冬氨酸受体(NMDAR)的NR2A和NR2B亚单位的自身抗体引起。这 突触受体在前脑神经元中高度表达，并在突触可塑性中起关键作用。 被认为是潜在的记忆存储的细胞过程。然而，NMDAR的过度活动可能会引发 兴奋毒性作用。我们的假设是，某些抗体起部分激动剂的作用，而另一些抗体起作用 NMDAR的拮抗剂，取决于与NR2A和NR2B亚基的相互作用模式。慢性暴露 抗NMDAR抗体会导致体内平衡失衡，最终导致含有NMDAR的 神经元。 我们的目标是确定一组鼠和人的抗NMDAR抗体的毒性潜力，后者已经被 选自从狼疮患者的脾细胞产生的组合文库或直接从抗原性 另外三名患者外周血中的B细胞。我们将通过隔离新的 人类，抗NMDAR抗体。我们将研究抗NMDAR抗体改变 NMDAR在海马神经元中的生理反应，海马区是NPSLE的关键脑区。 此外，我们将确定抗NR2抗体对大鼠突触可塑性的有害影响。 海马体。最后，我们将研究抗NMDAR抗体对行为小鼠进行一系列 认知任务依赖于NMDAR丰富的大脑区域的完整性。因此，我们将研究自身抗体是如何 影响大脑，从细胞到行为层面。 总体而言，我们相信这些研究将使我们能够确定抗NMDAR的作用机制 抗体会对大脑产生神经毒性作用。此外，我们还将了解反 NMDAR抗体对作为记忆处理基础的突触可塑性过程。 我们预见，这些研究可能与NPSLE的治疗方案相关。

Project 1: "Mechanisms of neurotoxicity of lupus anti-NMDAR antibodies: Electrophysiology to Behavior" (Huerta PI). The objective of this project is to examine whether key syndromes of neuropsychiatric lupus erythematosus (NPSLE) are caused by autoantibodies that bind the NR2A and NR2B subunits of the N-methyl-o-aspartate receptor (NMDAR). This synaptic receptor is highly expressed in forebrain neurons and is crucially involved in synaptic plasticity, which is regarded as the cellular process underlying memory storage. However, hyperactivity of the NMDAR can trigger excitotoxic effects. Our hypothesis is that certain antibodies function as partial agonists while others function as antagonists for the NMDAR, depending on the mode of interaction with the NR2A and NR2B subunits. Chronic exposure to the anti-NMDAR antibodies would lead to homeostatic imbalance and eventual death of the NMDAR-containing neurons. We aim to determine the toxic potential of a battery of murine and human anti-NMDAR antibodies, the latter having been selected either from a combinatorial library generated from spleen cells of a lupus patient or directly from antigenspecific peripheral blood B cells of three additional patients. We will expand our existing panel by isolating new human, anti-NMDAR antibodies. We will study the mechanisms by which the anti-NMDAR antibodies alter the physiological responses of the NMDAR in neurons of the hippocampus, a brain region critically targeted in NPSLE. Furthermore, we will determine the deleterious effects of the anti-NR2 antibodies over synaptic plasticity in the hippocampus. Finally, we will study the effects of anti-NMDAR antibodies on behaving mice performing a series of cognitive tasks that depend on the integrity of NMDAR-rich brain regions. Thus, we will examine how autoantibodies affect the brain, from the cellular to the behavioral level. Overall, we believe these studies will allow us to determine the functional mechanisms by which the antiNMDAR antibodies cause their neurotoxic effect in the brain. Moreover, we will gain an understanding of the effect of the anti- NMDAR antibodies on the synaptic plasticity processes that underlie memory processing. We foresee that these studies might be relevant for therapeutic protocols in NPSLE.