Motor axon output is controlled by Renshaw cells forming an inhibitory feedback circuit with spinal motoneurons that was first described by Birdsey Renshaw in 1941. Since then a large number of investigators have defined Renshaw cells connectivity, electrophysiological properties, actions on spinal motoneurons and interneurons and more recently their development and molecular genetics. However, up to date there is no consensus about how this recurrent inhibitory feedback circuit alters motor output, ongoing movement and motor actions. This gap in knowledge is important especially considering that the recurrent inhibitory circuit has been shown to fail in patients with high levels of spasticity due to stroke, spinal cord injury, amyotrophic lateral sclerosis (ALS) or hereditary spastic paresis. The P.I. also recently discovered that this circuit is disconnected in animal models of ALS and participated in a study that involucrate Renshaw cell dysfunction in Spinal Muscular Atrophy. It is clearly necessary to reexamine the exact role this circuit plays on the output of motor commands from the spinal cord. In this proposal we leverage new knowledge on the molecular biology and genetics of the Renshaw cell to develop animal models for specific silencing these cells in adult. We propose to use commercially available mouse models in a genetic intersectional approach based on co-expression of the parvalbumin (Pvalb) and calbindin (Calb1) genes and taking advantage of mice in which we can direct expression of reporter proteins, GiDREADDs or tetanus toxin under a dual conditional strategy based on co- expression of both cre and flp, each recombinase respectively dependent on Calb1 and Pvalb. We will also test new scAVV9 vectors for directing expression of dual conditional transgenes specifically in spinal cord neurons.
The aims of this exploratory R21 proposal is to develop and validate these models in Aims 1 and 2 and then use them to test the role of Renshaw cells mediated recurrent inhibition in desynchronization of motor output to diminish physiological tremor during muscle contractions (Aim 3). Validation of this animal model will be of great use to test in the future classical and new theories on Renshaw cells function and also their involvement in different diseases of the spinal cord motor system.

Public Health Relevance

Renshaw cell inhibitory control of motoneurons has been found altered in many motor spastic syndromes but their exact function has not been fully defined and their role in disease unclear. We propose to develop mouse models to alter Renshaw cell activity by directing expression of chemogenic inhibitory receptors or a synapse silencing toxin specifically in these cells. These models will be useful to more directly test Renshaw cells involvement in normal and abnormal motor output.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Exploratory/Developmental Grants (R21)
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Sensorimotor Integration Study Section (SMI)
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Chen, Daofen
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Emory University
Schools of Medicine
United States
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