The complement system is implicated in synapse loss in the MS hippocampus, but the functional consequences of synapse loss remain poorly understood. Here, in post-mortem MS hippocampi with demyelination we find that deposits of the complement component C1q are enriched in the CA2 subfield, are linked to loss of inhibitory synapses and are significantly higher in MS patients with cognitive impairments compared to those with preserved cognitive functions. Using the cuprizone mouse model of demyelination, we corroborated that C1q deposits are highest within the demyelinated dorsal hippocampal CA2 pyramidal layer, and co-localized with inhibitory synapses engulfed by microglia/macrophages. In agreement with the loss of inhibitory perisomatic synapses, we further found that Schaffer collateral feedforward inhibition but not excitation was impaired in CA2 pyramidal neurons and accompanied by a reduced spike output. Ultimately, we show that these electrophysiological changes were associated with an impaired encoding of social memories. Together, our findings identify CA2 as a critical circuit in demyelinated intrahippocampal lesions and memory dysfunctions in MS.

中文翻译：

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脱髓鞘海马中补体相关的CA2抑制性突触的丧失损害记忆

补体系统与MS海马突触丢失有关，但对突触丢失的功能后果知之甚少。在这里，在具有脱髓鞘的死后MS海马体中，我们发现补体成分C1q的沉积物富集在CA2子域中，与抑制性突触的损失有关，并且与具有保留认知功能的MS患者相比，具有认知障碍的MS患者明显更高。使用脱髓鞘的cuprizone小鼠模型，我们证实了C1q沉积物在脱髓鞘的背侧海马CA2锥体层内最高，并且与小胶质细胞/巨噬细胞吞噬的抑制性突触共同定位。与抑制性抑制的突触突触的丧失相一致，我们进一步发现，在CA2锥体神经元中，Schaffer侧支前馈抑制受到抑制，但没有受到刺激，并伴随着峰值输出减少。最终，我们证明了这些电生理变化与社交记忆编码受损有关。在一起，我们的研究结果确定CA2是MS脱髓鞘的海马内病变和记忆功能障碍的关键电路。