Conditional RAC1 knockout in motor neurons restores H-reflex rate-dependent depression after spinal cord injury

Abstract A major complication with spinal cord injury (SCI) is the development of spasticity, a clinical symptom of hyperexcitability within the spinal H-reflex pathway. We have previously demonstrated a common structural motif of dendritic spine dysgenesis associated with hyperexcitability disorder...

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Autores principales:	Curtis A. Benson, Kai-Lan Olson, Siraj Patwa, Marike L. Reimer, Lakshmi Bangalore, Myriam Hill, Stephen G. Waxman, Andrew M. Tan
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/8eead8da8f334be583b42fdfcc67a7df
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spelling	oai:doaj.org-article:8eead8da8f334be583b42fdfcc67a7df2021-12-02T14:25:55ZConditional RAC1 knockout in motor neurons restores H-reflex rate-dependent depression after spinal cord injury10.1038/s41598-021-87476-52045-2322https://doaj.org/article/8eead8da8f334be583b42fdfcc67a7df2021-04-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-87476-5https://doaj.org/toc/2045-2322Abstract A major complication with spinal cord injury (SCI) is the development of spasticity, a clinical symptom of hyperexcitability within the spinal H-reflex pathway. We have previously demonstrated a common structural motif of dendritic spine dysgenesis associated with hyperexcitability disorders after injury or disease insults to the CNS. Here, we used an adeno-associated viral (AAV)-mediated Cre-Lox system to knockout Rac1 protein expression in motor neurons after SCI. Three weeks after AAV9-Cre delivery into the soleus/gastrocnemius of Rac1-“floxed” adult mice to retrogradely infect spinal alpha-motor neurons, we observed significant restoration of RDD and reduced H-reflex excitability in SCI animals. Additionally, viral-mediated Rac1 knockdown reduced presence of dendritic spine dysgenesis on motor neurons. In control SCI animals without Rac1 knockout, we continued to observe abnormal dendritic spine morphology associated with hyperexcitability disorder, including an increase in mature, mushroom dendritic spines, and an increase in overall spine length and spine head size. Taken together, our results demonstrate that viral-mediated disruption of Rac1 expression in ventral horn motor neurons can mitigate dendritic spine morphological correlates of neuronal hyperexcitability, and reverse hyperreflexia associated with spasticity after SCI. Finally, our findings provide evidence of a putative mechanistic relationship between motor neuron dendritic spine dysgenesis and SCI-induced spasticity.Curtis A. BensonKai-Lan OlsonSiraj PatwaMarike L. ReimerLakshmi BangaloreMyriam HillStephen G. WaxmanAndrew M. TanNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-17 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Curtis A. Benson Kai-Lan Olson Siraj Patwa Marike L. Reimer Lakshmi Bangalore Myriam Hill Stephen G. Waxman Andrew M. Tan Conditional RAC1 knockout in motor neurons restores H-reflex rate-dependent depression after spinal cord injury
description	Abstract A major complication with spinal cord injury (SCI) is the development of spasticity, a clinical symptom of hyperexcitability within the spinal H-reflex pathway. We have previously demonstrated a common structural motif of dendritic spine dysgenesis associated with hyperexcitability disorders after injury or disease insults to the CNS. Here, we used an adeno-associated viral (AAV)-mediated Cre-Lox system to knockout Rac1 protein expression in motor neurons after SCI. Three weeks after AAV9-Cre delivery into the soleus/gastrocnemius of Rac1-“floxed” adult mice to retrogradely infect spinal alpha-motor neurons, we observed significant restoration of RDD and reduced H-reflex excitability in SCI animals. Additionally, viral-mediated Rac1 knockdown reduced presence of dendritic spine dysgenesis on motor neurons. In control SCI animals without Rac1 knockout, we continued to observe abnormal dendritic spine morphology associated with hyperexcitability disorder, including an increase in mature, mushroom dendritic spines, and an increase in overall spine length and spine head size. Taken together, our results demonstrate that viral-mediated disruption of Rac1 expression in ventral horn motor neurons can mitigate dendritic spine morphological correlates of neuronal hyperexcitability, and reverse hyperreflexia associated with spasticity after SCI. Finally, our findings provide evidence of a putative mechanistic relationship between motor neuron dendritic spine dysgenesis and SCI-induced spasticity.
format	article
author	Curtis A. Benson Kai-Lan Olson Siraj Patwa Marike L. Reimer Lakshmi Bangalore Myriam Hill Stephen G. Waxman Andrew M. Tan
author_facet	Curtis A. Benson Kai-Lan Olson Siraj Patwa Marike L. Reimer Lakshmi Bangalore Myriam Hill Stephen G. Waxman Andrew M. Tan
author_sort	Curtis A. Benson
title	Conditional RAC1 knockout in motor neurons restores H-reflex rate-dependent depression after spinal cord injury
title_short	Conditional RAC1 knockout in motor neurons restores H-reflex rate-dependent depression after spinal cord injury
title_full	Conditional RAC1 knockout in motor neurons restores H-reflex rate-dependent depression after spinal cord injury
title_fullStr	Conditional RAC1 knockout in motor neurons restores H-reflex rate-dependent depression after spinal cord injury
title_full_unstemmed	Conditional RAC1 knockout in motor neurons restores H-reflex rate-dependent depression after spinal cord injury
title_sort	conditional rac1 knockout in motor neurons restores h-reflex rate-dependent depression after spinal cord injury
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/8eead8da8f334be583b42fdfcc67a7df
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Conditional RAC1 knockout in motor neurons restores H-reflex rate-dependent depression after spinal cord injury

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