Neurotransmission defects and motoneuron degeneration are hallmarks of spinal muscular atrophy, a monogenetic disease caused by the deficiency of the SMN protein. In the present study, we show that systemic application of R-Roscovitine, a Ca_v2.1/Ca_v2.2 channel modifier and a cyclin-dependent kinase 5 (Cdk-5) inhibitor, significantly improved survival of SMA mice. In addition, R-Roscovitine increased Ca_v2.1 channel density and sizes of the motor endplates. In vitro, R-Roscovitine restored axon lengths and growth cone sizes of Smn-deficient motoneurons corresponding to enhanced spontaneous Ca²⁺ influx and elevated Ca_v2.2 channel cluster formations independent of its capability to inhibit Cdk-5. Acute application of R-Roscovitine at the neuromuscular junction significantly increased evoked neurotransmitter release, increased the frequency of spontaneous miniature potentials, and lowered the activation threshold of silent terminals. These data indicate that R-Roscovitine improves Ca²⁺ signaling and Ca²⁺ homeostasis in Smn-deficient motoneurons, which is generally crucial for motoneuron differentiation, maturation, and function.

神经传递缺陷和运动神经元变性是脊髓肌萎缩的标志，脊髓肌萎缩是由SMN蛋白缺乏引起的单基因疾病。在本研究中，我们显示R-Roscovitine，Ca _v 2.1 / Ca _v 2.2通道调节剂和细胞周期蛋白依赖性激酶5（Cdk-5）抑制剂的全身应用显着提高了SMA小鼠的存活率。此外，R-Roscovitine增加了Ca _v 2.1通道密度和电机端板尺寸。在体外，R-Roscovitine恢复了Smn缺失的运动神经元的轴突长度和生长锥大小，这对应于自发Ca ^2+内流增加和Ca _v升高2.2通道簇的形成与其抑制Cdk-5的能力无关。R-Roscovitine在神经肌肉接头处的急性应用显着增加了诱发的神经递质的释放，增加了自发微型电位的频率，并降低了沉默末端的激活阈值。这些数据表明，R-Roscovitine可改善Smn缺失的运动神经元中的Ca ²⁺信号传导和Ca ²⁺稳态，这对于运动神经元的分化，成熟和功能通常至关重要。