Zhu Hongmei, Dalvi Urvashi, Cazenave William, Cattaert Daniel, Branchereau Pascal
University Bordeaux, CNRS, INCIA, UMR 5287, Bordeaux, France.
J Physiol. 2024 Mar;602(5):913-932. doi: 10.1113/JP285105. Epub 2024 Feb 12.
Amyotrophic lateral sclerosis (ALS) is a fatal adult-onset neurodegenerative disease characterized by progressive motor neuron degeneration and muscle paralysis. Recent evidence suggests the dysfunction of inhibitory signalling in ALS motor neurons. We have shown that embryonic day (E)17.5 spinal motoneurons (MNs) of the SOD1 mouse model of ALS exhibit an altered chloride homeostasis. At this prenatal stage, inhibition of spinal motoneurons (MNs) is mediated by depolarizing GABAergic/glycinergic postsynaptic potentials (dGPSPs). Here, using an ex vivo preparation and patch clamp recording from MNs with a chloride equilibrium set below spike threshold, we report that low input resistance (R ) E17.5 MNs from the SOD1 ALS mouse model do not correctly integrate dGPSPs evoked by electrical stimulations of GABA/glycine inputs at different frequencies. Indeed, firing activity of most wild-type (WT) MNs with low R was inhibited by incoming dGPSPs, whereas low R SOD1 MNs were excited or exhibited a dual response (excited by low frequency dGPSPs and inhibited by high frequency dGPSPs). Simulation highlighted the importance of the GABA/glycine input density and showed that pure excitation could be obtained in SOD-like MNs by moving GABA/glycine input away from the cell body to dendrites. This was in agreement with confocal imaging showing a lack of peri-somatic inhibitory terminals in SOD1 MNs compared to WT littermates. Putative fast ALS-vulnerable MNs with low R are therefore lacking functional inhibition at the near-term prenatal stage. KEY POINTS: We analysed the integration of GABAergic/glycinergic synaptic events by embryonic spinal motoneurons (MNs) in a mouse model of the amyotrophic lateral sclerosis (ALS) neurodegenerative disease. We found that GABAergic/glycinergic synaptic events do not properly inhibit ALS MNs with low input resistance, most probably corresponding to future vulnerable MNs. We used a neuron model to highlight the importance of the GABA/glycine terminal location and density in the integration of the GABAergic/glycinergic synaptic events. Confocal imaging showed a lack of GABA/glycine terminals on the cell body of ALS MNs. The present study suggests that putative ALS vulnerable MNs with low R lack functional inhibition at the near-term stage.
肌萎缩侧索硬化症（ALS）是一种致命的成人发病的神经退行性疾病，其特征为进行性运动神经元变性和肌肉麻痹。最近的证据表明ALS运动神经元中抑制性信号传导功能障碍。我们已经表明，ALS的SOD1小鼠模型胚胎期（E）17.5的脊髓运动神经元（MNs）表现出氯离子稳态改变。在这个产前阶段，脊髓运动神经元（MNs）的抑制是由去极化的GABA能/甘氨酸能突触后电位（dGPSPs）介导的。在这里，我们使用离体标本，并对氯离子平衡设定在动作电位阈值以下的MNs进行膜片钳记录，我们报告说，来自SOD1 ALS小鼠模型的低输入电阻（R）的E17.5 MNs不能正确整合由不同频率的GABA/甘氨酸输入电刺激诱发的dGPSPs。事实上，大多数低R的野生型（WT）MNs的放电活动被传入的dGPSPs抑制，而低R的SOD1 MNs则被兴奋或表现出双重反应（被低频dGPSPs兴奋，被高频dGPSPs抑制）。模拟突出了GABA/甘氨酸输入密度的重要性，并表明通过将GABA/甘氨酸输入从细胞体移至树突，可以在类似SOD的MNs中获得纯兴奋。这与共聚焦成像结果一致，该成像显示与野生型同窝小鼠相比，SOD1 MNs缺乏胞体周围的抑制性终末。因此，具有低R的假定快速ALS易损MNs在产前近期阶段缺乏功能性抑制。
我们分析了肌萎缩侧索硬化症（ALS）神经退行性疾病小鼠模型中胚胎脊髓运动神经元（MNs）对GABA能/甘氨酸能突触事件的整合。我们发现，GABA能/甘氨酸能突触事件不能正确抑制低输入电阻的ALS MNs，最有可能对应于未来易损的MNs。我们使用神经元模型突出了GABA/甘氨酸终末位置和密度在GABA能/甘氨酸能突触事件整合中的重要性。共聚焦成像显示ALS MNs的细胞体上缺乏GABA/甘氨酸终末。本研究表明，具有低R的假定ALS易损MNs在近期阶段缺乏功能性抑制。
