TY - JOUR
T1 - RhoA-ROCK Inhibition Reverses Synaptic Remodeling and Motor and Cognitive Deficits Caused by Traumatic Brain Injury
AU - Mulherkar, Shalaka
AU - Firozi, Karen
AU - Huang, Wei
AU - Uddin, Mohammad Danish
AU - Grill, Raymond J.
AU - Costa-Mattioli, Mauro
AU - Robertson, Claudia
AU - Tolias, Kimberley F.
N1 - Funding Information:
This work was supported by grants from the DoD (W81XWH0820148), the NIH (R01NS062829), and the Mission Connect-TIRR Foundation (K.F.T.) and NIMH (096816), NINDS (076708) and the Department of Defense (AR120254) to M.C.-M. S.M. is supported by an Angelman Syndrome Foundation Postdoctoral fellowship. We received technical assistance from the BCM RNA In Situ Hybridization Core (funded by NIH grants 1S10 OD016167 and 1U54 HD083092), the BCM Pathology Core (funded by NIH grant 5P30HD 024064), and the Neurobehavioral Core (NICHD, U54HD083092). We thank F. Liu and Cheng-lin (Vivian) Shaw for technical help and S. Gaddam and S. Pillai for guidance with surgeries.
Publisher Copyright:
© 2017 The Author(s).
PY - 2017/12/1
Y1 - 2017/12/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85028920014&partnerID=8YFLogxK
U2 - 10.1038/s41598-017-11113-3
DO - 10.1038/s41598-017-11113-3
M3 - Article
C2 - 28878396
AN - SCOPUS:85028920014
SN - 2045-2322
VL - 7
JO - Scientific Reports
JF - Scientific Reports
IS - 1
M1 - 10689
ER -