Chronic Pharmacological Increase of Neuronal Activity Improves Sensory-Motor Dysfunction in Spinal Muscular Atrophy Mice

• Published in: The Journal of neuroscience 2021-01, Vol.41 (2), p.376-389
• Main Authors: Simon, Christian M, Blanco-Redondo, Beatriz, Buettner, Jannik M, Pagiazitis, John G, Fletcher, Emily V, Sime Longang, Josiane K, Mentis, George Z
• Format: Article
• Language: English
• Subjects: 4-Aminopyridine - therapeutic use; Animals; Atrophy; Cell death; Cell Death - drug effects; Circuits; Death; Disease; Health services; In vivo methods and tests; Mice; Mice, Knockout; Mortality; Motor Neurons - drug effects; Movement Disorders - drug therapy; Movement Disorders - etiology; Movement Disorders - psychology; Muscles; Muscular Atrophy, Spinal - complications; Muscular Atrophy, Spinal - drug therapy; Muscular Atrophy, Spinal - psychology; Neural networks; Neurodegenerative diseases; Neuromuscular Junction - drug effects; Neuromuscular junctions; Neurotransmission; p53 Protein; Pharmacology; Phenotypes; Potassium; Potassium Channel Blockers - therapeutic use; Proprioception; Proprioception - drug effects; Psychomotor Performance - drug effects; Sensation Disorders - drug therapy; Sensation Disorders - etiology; Sensation Disorders - psychology; Sensorimotor integration; Sexual behavior; Skeletal muscle; SMN protein; Spinal muscular atrophy; Survival of Motor Neuron 1 Protein - genetics; Synapses; Synapses - drug effects; Synaptic Transmission - drug effects; Tumor Suppressor Protein p53 - antagonists & inhibitors
• ISSN: 0270-6474; 1529-2401
• DOI: 10.1523/JNEUROSCI.2142-20.2020

Dysfunction of neuronal circuits is an important determinant of neurodegenerative diseases. Synaptic dysfunction, death, and intrinsic activity of neurons are thought to contribute to the demise of normal behavior in the disease state. However, the interplay between these major pathogenic events during disease progression is poorly understood. Spinal muscular atrophy (SMA) is a neurodegenerative disease caused by a deficiency in the ubiquitously expressed protein SMN and is characterized by motor neuron death, skeletal muscle atrophy, as well as dysfunction and loss of both central and peripheral excitatory synapses. These disease hallmarks result in an overall reduction of neuronal activity in the spinal sensory-motor circuit. Here, we show that increasing neuronal activity by chronic treatment with the FDA-approved potassium channel blocker 4-aminopyridine (4-AP) improves motor behavior in both sexes of a severe mouse model of SMA. 4-AP restores neurotransmission and number of proprioceptive synapses and neuromuscular junctions (NMJs), while having no effects on motor neuron death. In addition, 4-AP treatment with pharmacological inhibition of p53-dependent motor neuron death results in additive effects, leading to full correction of sensory-motor circuit pathology and enhanced phenotypic benefit in SMA mice. Our study reveals that 4-AP-induced increase of neuronal activity restores synaptic connectivity and function in the sensory-motor circuit to improve the SMA motor phenotype. Spinal muscular atrophy (SMA) is a neurodegenerative disease, characterized by synaptic loss, motor neuron death, and reduced neuronal activity in spinal sensory-motor circuits. However, whether these are parallel or dependent events is unclear. We show here that long-term increase of neuronal activity by the FDA-approved drug 4-aminopyridine (4-AP) rescues the number and function of central and peripheral synapses in a SMA mouse model, resulting in an improvement of the sensory-motor circuit and motor behavior. Combinatorial treatment of pharmacological inhibition of p53, which is responsible for motor neuron death and 4-AP, results in additive beneficial effects on the sensory-motor circuit in SMA. Thus, neuronal activity restores synaptic connections and improves significantly the severe SMA phenotype.