Motor circuits control fundamental behaviors such as swallowing, breathing and locomotion. Spinal motor neurons are the key mediators translating motor commands generated within the central nervous system to peripheral muscle targets. Motor neurons are activated by a precisely regulated pattern of synaptic activity from sensory neurons, local spinal interneurons and descending pathways from the brain. During early development, synaptic activity received by motor neurons shapes their functional properties. In contrast, gene mutations that induce perturbations in either neuronal wiring or synaptic drive received by motor neurons often result in motor system disorders. A prominent example of this situation is spinal muscular atrophy (SMA)?an inherited neuromuscular disease caused by ubiquitous deficiency in the survival motor neuron (SMN) protein. SMA pathogenesis involves alterations of multiple components of the motor circuit leading to abnormalities in spinal reflexes, motor neuron loss and skeletal muscle atrophy. However, the molecular, cellular and circuit mechanisms underlying SMA remain largely elusive. Our previous work have led us in uncovering novel molecular perturbations involving the downregulation of the delayed rectifier potassium channel Kv2.1 as an important determinant in the regulation of motor neuron firing. In addition, SMA motor neurons are under increased tonic inhibitory originating from pre-motor inhibitory interneurons. Finally, we have identified reduction of neurotrophin 3 (NT3) as a candidate for the selective vulnerability of motor circuits responsible for activating proximal muscles which are more vulnerable compared to distal muscles.
In Aim 1, we will study whether increased inhibitory synaptic drive on motor neurons, acting non-cell autonomously, is responsible for motor circuit dysfunction in SMA mice. We will employ mouse genetics together with morphological and functional assays.
In Aim 2, we will investigate whether the dynamic downregulation of the potassium delayed rectifier channel Kv2.1 expression through abnormal dephopshorylation is a major contributor for the reduction in MN repetitive firing in SMA. We will use ES-differentiated motor neurons co-cultured with interneurons that have been engineered to downregulate SMN protein levels following antibiotic exposure. In addition, we will use mouse models to determine the contribution of the main three enzymes reported to regulate Kv2.1 expression in neurons.
In Aim 3, we will expand on our preliminary studies, which has identified reduction of NT3 in SMA spinal cords early in the disease onset, to determine its relative contribution in the selective vulnerability of motor circuits in SMA mice. Specific and selective upregulation of NT3 in motor neurons or muscles will provide further insights into the source of NT3 impairment.

Public Health Relevance

Neuronal control of movement is extensively studied not only because it underlies fundamental human behaviors but also because diseases that affect the motor system represent a significant burden for human health. We have identified abnormalities in excitatory/inhibitory balance on motor neurons as well as possible reduction in trophic support offered by neurotrophic factors with important implications in the normal function and disease of the motor system. This proposal describes a multidisciplinary effort aimed to determine the molecular, cellular and neuronal circuit mechanisms that may contribute to human diseases such as SMA?the leading genetic cause of death in infancy.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
Project #
Application #
Study Section
Cell Death in Neurodegeneration Study Section (CDIN)
Program Officer
Nuckolls, Glen H
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Columbia University (N.Y.)
Schools of Medicine
New York
United States
Zip Code
Van Alstyne, Meaghan; Simon, Christian M; Sardi, S Pablo et al. (2018) Dysregulation of Mdm2 and Mdm4 alternative splicing underlies motor neuron death in spinal muscular atrophy. Genes Dev 32:1045-1059
Cantor, Sarah; Zhang, Wei; Delestrée, Nicolas et al. (2018) Preserving neuromuscular synapses in ALS by stimulating MuSK with a therapeutic agonist antibody. Elife 7:
Simon, Christian M; Dai, Ya; Van Alstyne, Meaghan et al. (2017) Converging Mechanisms of p53 Activation Drive Motor Neuron Degeneration in Spinal Muscular Atrophy. Cell Rep 21:3767-3780
Fletcher, Emily V; Simon, Christian M; Pagiazitis, John G et al. (2017) Reduced sensory synaptic excitation impairs motor neuron function via Kv2.1 in spinal muscular atrophy. Nat Neurosci 20:905-916
Bikoff, Jay B; Gabitto, Mariano I; Rivard, Andre F et al. (2016) Spinal Inhibitory Interneuron Diversity Delineates Variant Motor Microcircuits. Cell 165:207-219
Simon, Christian M; Janas, Anna M; Lotti, Francesco et al. (2016) A Stem Cell Model of the Motor Circuit Uncouples Motor Neuron Death from Hyperexcitability Induced by SMN Deficiency. Cell Rep 16:1416-1430
Mende, Michael; Fletcher, Emily V; Belluardo, Josephine L et al. (2016) Sensory-Derived Glutamate Regulates Presynaptic Inhibitory Terminals in Mouse Spinal Cord. Neuron 90:1189-1202
Sharma, Aarti; Lyashchenko, Alexander K; Lu, Lei et al. (2016) ALS-associated mutant FUS induces selective motor neuron degeneration through toxic gain of function. Nat Commun 7:10465
Remédio, Leonor; Gribble, Katherine D; Lee, Jennifer K et al. (2016) Diverging roles for Lrp4 and Wnt signaling in neuromuscular synapse development during evolution. Genes Dev 30:1058-69
de Nooij, Joriene C; Simon, Christian M; Simon, Anna et al. (2015) The PDZ-domain protein Whirlin facilitates mechanosensory signaling in mammalian proprioceptors. J Neurosci 35:3073-84

Showing the most recent 10 out of 13 publications