GSE112771
R-Roscovitine improves motoneuron function in mouse models for Spinal Muscular Atrophy.
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 Cav2.1 / Cav2.2 channel modifier and a Cyclin-dependent kinase 5 (Cdk-5) inhibitor - significantly improved survival of SMA mice. In addition, R-Roscovitine increased Cav2.1 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 Cav2.2 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, 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. Overall design: Smn+/+;SMN2 (Smn_p_p) and Smn-/-;SMN2 (Smn_m_m)  motoneurons treated with R-Roscovitine (plus_R1-3) and controls (minus_R1-3). Total number of samples is 12