Catecholaminergic dysfunction drives postural and locomotor deficits in a mouse model of spinal muscular atrophy

John G Pagiazitis; Nicolas Delestrée; Leonie Sowoidnich; Nandhini Sivakumar; Christian M Simon; Athanasios Chatzisotiriou; Maria Albani; George Z Mentis

doi:10.1016/j.celrep.2024.115147

Catecholaminergic dysfunction drives postural and locomotor deficits in a mouse model of spinal muscular atrophy

Cell Rep. 2025 Jan 2;44(1):115147. doi: 10.1016/j.celrep.2024.115147. Online ahead of print.

Authors

John G Pagiazitis¹, Nicolas Delestrée², Leonie Sowoidnich³, Nandhini Sivakumar², Christian M Simon⁴, Athanasios Chatzisotiriou⁵, Maria Albani⁵, George Z Mentis⁶

Affiliations

¹ Center for Motor Neuron Biology and Disease, Columbia University, New York, NY 10032, USA; Department of Neurology, Columbia University, New York, NY 10032, USA; Department of Physiology, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki 541 24, Greece.
² Center for Motor Neuron Biology and Disease, Columbia University, New York, NY 10032, USA; Department of Neurology, Columbia University, New York, NY 10032, USA.
³ Center for Motor Neuron Biology and Disease, Columbia University, New York, NY 10032, USA; Department of Neurology, Columbia University, New York, NY 10032, USA; Carl-Ludwig-Institute for Physiology, Leipzig University, Leipzig, Germany.
⁴ Carl-Ludwig-Institute for Physiology, Leipzig University, Leipzig, Germany.
⁵ Department of Physiology, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki 541 24, Greece.
⁶ Center for Motor Neuron Biology and Disease, Columbia University, New York, NY 10032, USA; Department of Neurology, Columbia University, New York, NY 10032, USA; Department of Pathology and Cell Biology, Columbia University, New York, NY 10032, USA. Electronic address: [email protected].

PMID: 39752251
DOI: 10.1016/j.celrep.2024.115147

Abstract

Development and maintenance of posture is essential behavior for overground mammalian locomotion. Dopamine and noradrenaline strongly influence locomotion, and their dysregulation initiates the development of motor impairments linked to neurodegenerative disease. However, the precise cellular and circuit mechanisms are not well defined. Here, we investigated the role of catecholaminergic neuromodulation in a mouse model of spinal muscular atrophy (SMA). SMA is characterized by severe motor dysfunction and postural deficits. We identify progressive loss of catecholaminergic synapses from spinal neurons that occur via non-cell autonomous mechanisms. Importantly, the selective restoration of survival motor neuron (SMN) in either catecholaminergic or serotonergic neurons is sufficient to correct impairments in locomotion. However, only combined SMN restoration in both catecholaminergic and serotonergic neurons or pharmacological treatment with l-dopa improve the severe postural deficits. These findings uncover the synaptic and cellular mechanisms responsible for the postural and motor symptoms in SMA and identify catecholaminergic neuromodulation as a potential therapeutic target.

Keywords: CP: Neuroscience; L-dopa; dopamine; locomotion; motor neuron; neurodegenerative disease; neuromodulation; noradrenaline; spinal muscular atrophy; synapse; ventral spinocerebellar tract neuron.