Department of Neurology Focus Program Translational Neurosciences (FTN) and Immunotherapy (FZI), Rhine-Main Neuroscience Network (rmn²), University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany.
Focus Program Translational Neurosciences & Institute of Pathophysiology, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany.
Nat Neurosci. 2018 Oct;21(10):1392-1403. doi: 10.1038/s41593-018-0193-2. Epub 2018 Sep 26.
Multiple sclerosis (MS) patients exhibit neuropsychological symptoms in early disease despite the immune attack occurring predominantly in white matter and spinal cord. It is unclear why neurodegeneration may start early in the disease and is prominent in later stages. We assessed cortical microcircuit activity by employing spiking-specific two-photon Ca imaging in proteolipid protein-immunized relapsing-remitting SJL/J mice in vivo. We identified the emergence of hyperactive cortical neurons in remission only, independent of direct immune-mediated damage and paralleled by elevated anxiety. High levels of neuronal activity were accompanied by increased caspase-3 expression. Cortical TNFα expression was mainly increased by excitatory neurons in remission; blockade with intraventricular infliximab restored AMPA spontaneous excitatory postsynaptic current frequencies, completely recovered normal neuronal network activity patterns and alleviated elevated anxiety. This suggests a dysregulation of cortical networks attempting to achieve functional compensation by synaptic plasticity mechanisms, indicating a link between immune attack and early start of neurodegeneration.
多发性硬化症（MS）患者在疾病早期表现出神经心理学症状，尽管免疫攻击主要发生在白质和脊髓中。目前尚不清楚为什么神经退行性变可能在疾病早期开始，并在后期阶段更为突出。我们通过在体内对复发性缓解 SJL/J 小鼠进行针对尖峰的双光子 Ca 成像来评估皮质微电路活动。我们发现，仅在缓解期出现皮质神经元过度活跃，与直接免疫介导的损伤无关，并伴有焦虑升高。高神经元活性伴随着 caspase-3 表达的增加。皮质 TNFα 的表达主要是由缓解期的兴奋性神经元增加引起的；脑室内 infliximab 的阻断恢复了 AMPA 自发性兴奋性突触后电流频率，完全恢复了正常的神经元网络活动模式，并缓解了焦虑升高。这表明皮质网络的失调试图通过突触可塑性机制来实现功能补偿，表明免疫攻击与神经退行性变的早期开始之间存在联系。
