Non-canonical adrenergic neuromodulation of motoneuron intrinsic excitability through beta-receptors in wild-type and ALS mice

Altered neuronal excitability and synaptic inputs to motoneurons are part of the pathophysiology of Amyotrophic Lateral Sclerosis. The cAMP/PKA pathway regulates both of them but therapeutic interventions at this level are limited by the lack of knowledge about suitable pharmacological entry points. Here we used transcriptomics on microdissected and in situ motoneurons to reveal the modulation of PKA-coupled receptorome in SOD1(G93A) ALS mice, vs WT, demonstrating the dysregulation of multiple PKA-coupled GPCRs, in particular on vulnerable MNs, and the relative sparing of beta-adrenergic receptors. In vivo MN electrophysiology showed that beta2/beta3 agonists acutely increase excitability, in particular the input/output relationship, demonstrating a non-canonical adrenergic neuromodulation mediated by beta2/beta3 receptors both in WT and SOD1 mice. The excitability increase corresponds to the upregulation of immediate-early gene expression and dysregulation of ion channels transcriptome. However the beta2/beta3 neuromodulation is submitted to a strong homeostasis, since a ten days delivery of beta2/beta3 agonists results in an abolition of the excitability increase. The homeostatic response is largely caused by a substantial downregulation of PKA-coupled GPCRs in MNs from WT and SOD1 mice. Thus, beta-adrenergic receptors are physiologically involved in the regulation of MN excitability and transcriptomics, but, intriguingly, a strong homeostatic response is triggered upon chronic pharmacologic intervention. ### Competing Interest Statement The authors have declared no competing interest.