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
Affiliations
John G. Pagiazitis
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
Nicolas Delestrée
Center for Motor Neuron Biology and Disease, Columbia University, New York, NY 10032, USA; Department of Neurology, Columbia University, New York, NY 10032, USA
Leonie Sowoidnich
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
Nandhini Sivakumar
Center for Motor Neuron Biology and Disease, Columbia University, New York, NY 10032, USA; Department of Neurology, Columbia University, New York, NY 10032, USA
Christian M. Simon
Carl-Ludwig-Institute for Physiology, Leipzig University, Leipzig, Germany
Athanasios Chatzisotiriou
Department of Physiology, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki 541 24, Greece
Maria Albani
Department of Physiology, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki 541 24, Greece
George Z. Mentis
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; Corresponding author
Summary: 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.
