Université de Paris, Saints-Pères Paris Institute for the Neurosciences (SPPIN), Centre National de la Recherche Scientifique (CNRS), Paris, France.
Department of Neurology, Ulm University, Ulm, Germany.
J Exp Med. 2020 Aug 3;217(8). doi: 10.1084/jem.20191734.
Excessive excitation is hypothesized to cause motoneuron (MN) degeneration in amyotrophic lateral sclerosis (ALS), but actual proof of hyperexcitation in vivo is missing, and trials based on this concept have failed. We demonstrate, by in vivo single-MN electrophysiology, that, contrary to expectations, excitatory responses evoked by sensory and brainstem inputs are reduced in MNs of presymptomatic mutSOD1 mice. This impairment correlates with disrupted postsynaptic clustering of Homer1b, Shank, and AMPAR subunits. Synaptic restoration can be achieved by activation of the cAMP/PKA pathway, by either intracellular injection of cAMP or DREADD-Gs stimulation. Furthermore, we reveal, through independent control of signaling and excitability allowed by multiplexed DREADD/PSAM chemogenetics, that PKA-induced restoration of synapses triggers an excitation-dependent decrease in misfolded SOD1 burden and autophagy overload. In turn, increased MN excitability contributes to restoring synaptic structures. Thus, the decrease of excitation to MN is an early but reversible event in ALS. Failure of the postsynaptic site, rather than hyperexcitation, drives disease pathobiochemistry.
过度兴奋被假设会导致肌萎缩侧索硬化症（ALS）中的运动神经元（MN）变性，但体内过度兴奋的实际证据缺失，并且基于这一概念的试验已经失败。我们通过体内单个 MN 电生理学证明，与预期相反，感觉和脑干输入引发的兴奋性反应在先兆 mutSOD1 小鼠的 MN 中减少。这种损伤与 Homer1b、Shank 和 AMPAR 亚基的突触后聚集破坏有关。通过激活 cAMP/PKA 途径，无论是通过细胞内注射 cAMP 还是 DREADD-Gs 刺激，都可以实现突触的恢复。此外，我们通过复用 DREADD/PSAM 化学遗传学允许的信号和兴奋性的独立控制揭示，PKA 诱导的突触恢复会引发依赖于兴奋的错误折叠 SOD1 负担和自噬过载的减少。反过来，增加的 MN 兴奋性有助于恢复突触结构。因此，MN 兴奋的降低是 ALS 的早期但可逆转事件。突触后部位的衰竭，而不是过度兴奋，驱动疾病的病理生物化学。
