Abstract
Traumatic brain injury (TBI) causes extensive neural damage, often resulting in long-term cognitive impairments. Unfortunately, effective treatments for TBI remain elusive. The RhoA-ROCK signaling pathway is a potential therapeutic target since it is activated by TBI and can promote the retraction of dendritic spines/synapses, which are critical for information processing and memory storage. To test this hypothesis, RhoA-ROCK signaling was blocked by RhoA deletion from postnatal neurons or treatment with the ROCK inhibitor fasudil. We found that TBI impairs both motor and cognitive performance and inhibiting RhoA-ROCK signaling alleviates these deficits. Moreover, RhoA-ROCK inhibition prevents TBI-induced spine remodeling and mature spine loss. These data argue that TBI elicits pathological spine remodeling that contributes to behavioral deficits by altering synaptic connections, and RhoA-ROCK inhibition enhances functional recovery by blocking this detrimental effect. As fasudil has been safely used in humans, our results suggest that it could be repurposed to treat TBI.
Highlights
A promising approach for enhancing recovery following Traumatic brain injury (TBI) involves modulating the activity of small Rho-family GTPases[6, 7]
We show that TBI causes substantial motor, learning, and memory impairments in adult mice, which are alleviated by blocking RhoA-ROCK signaling via RhoA deletion from postnatal neurons or by treating mice with the ROCK inhibitor fasudil
We showed that TBI causes motor and cognitive impairments in mice that are alleviated by genetically or pharmacologically blocking RhoA-ROCK signaling
Summary
Shalaka Mulherkar[1], Karen Firozi[1], Wei Huang[1,6], Mohammad Danish Uddin[1], Raymond J. The RhoA-ROCK signaling pathway is a potential therapeutic target since it is activated by TBI and can promote the retraction of dendritic spines/synapses, which are critical for information processing and memory storage. Inhibiting RhoA or its key downstream effector Rho kinase (ROCK) in rodent models of spinal cord injury reduces inflammation and neuronal apoptosis and accelerates axonal regrowth, enhancing functional recovery[17] Blockade of this pathway improves spatial and working memory in aged rats and rat models of Alzheimer’s disease and promotes recovery of neurological function in human patients following ischemic stroke[18,19,20]. Our data suggest that TBI elicits pathological spine remodeling that likely contributes to behavioral deficits due to loss and/or alteration of established synaptic connections, and that inhibiting RhoA-ROCK signaling enhances functional recovery by blocking this detrimental effect
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