A critical role of Rho-kinase ROCK2 in the regulation of spine and synaptic function.
The actin cytoskeleton is critically involved in the regulation of the dendritic spine and synaptic properties, but the molecular mechanisms underlying actin dynamics in neurons are poorly defined. We took genetic approaches to create and analyze knockout mice specifically lacking ROCK2, a protein kinase that directly interacts with and is activated by the Rho GTPases, the central mediator of actin reorganization. We demonstrated that while these knockout mice were normal in gross brain anatomy, they were impaired in both basal synaptic transmission and hippocampal long-term potentiation (LTP). Consistent with the electrophysiological deficits, the ROCK2 knockout neurons showed deficits in spine properties, synapse density, the actin cytoskeleton, and the actin-binding protein cofilin. These results indicate that ROCK2/cofilin signaling is critical in the regulation of neuronal actin, spine morphology and synaptic function.
Zhou
Zikai
Z
Neurosciences and Mental Health, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, Canada M5G 1X8.
Meng
Yanghong
Y
Asrar
Suhail
S
Todorovski
Zarko
Z
Jia
Zhengping
Z
D051339:Actin Depolymerizing Factors / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D001703:Biophysics; D002478:Cells, Cultured; D049229:Dendritic Spines / Q000378:metabolism / Q000502:physiology* / Q000648:ultrastructure; D004558:Electric Stimulation; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D005998:Glycine / Q000494:pharmacology; D018684:Glycine Agents / Q000494:pharmacology; D006624:Hippocampus / Q000166:cytology; D066298:In Vitro Techniques; D017774:Long-Term Potentiation / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D046529:Microscopy, Electron, Transmission / Q000379:methods; D016202:N-Methylaspartate / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000648:ultrastructure*; D018408:Patch-Clamp Techniques; D010590:Phalloidine / Q000378:metabolism; D013569:Synapses / Q000502:physiology* / Q000648:ultrastructure; D016704:Synapsins / Q000378:metabolism; D050598:Vesicular Glutamate Transport Protein 1 / Q000378:metabolism; D054460:rho-Associated Kinases / Q000172:deficiency / Q000502:physiology*
D051339:Actin Depolymerizing Factors; D018690:Excitatory Amino Acid Agonists; D018684:Glycine Agents; D016704:Synapsins; D050598:Vesicular Glutamate Transport Protein 1; D010590:Phalloidine; D016202:N-Methylaspartate; C515855:Rock2 protein, mouse; D054460:rho-Associated Kinases; D005998:Glycine