An activity-regulated microRNA controls dendritic plasticity by down-regulating p250GAP

doi:10.1073/pnas.0803072105

An activity-regulated microRNA controls dendritic plasticity by down-regulating p250GAP

*Department of Veterinary Anatomy, Physiology, and Pharmacology, Washington State University, 100 Dairy Road, Pullman, WA 99164;
^†Vollum Institute,
**Cell and Developmental Biology,
^§Oregon Stem Cell Center, and
^‖Center for Study of Weight Regulation, Oregon Health and Science University, 3181 Sam Jackson Park Road, Portland, OR 97239; and
^¶Department of Neuroscience, Ohio State University, Columbus, OH 43210

Contributed by Richard H. Goodman, April 9, 2008 (received for review February 28, 2008)

Abstract

Activity-regulated gene expression is believed to play a key role in the development and refinement of neuronal circuitry. Nevertheless, the transcriptional networks that regulate synapse growth and plasticity remain largely uncharacterized. Here, we show that microRNA 132 (miR132) is an activity-dependent rapid response gene regulated by the cAMP response element-binding (CREB) protein pathway. Introduction of miR132 into hippocampal neurons enhanced dendrite morphogenesis whereas inhibition of miR132 by 2′O-methyl RNA antagonists blocked these effects. Furthermore, neuronal activity inhibited translation of p250GAP, a miR132 target, and siRNA-mediated knockdown of p250GAP mimicked miR132-induced dendrite growth. Experiments using dominant-interfering mutants suggested that Rac signaling is downstream of miR132 and p250GAP. We propose that the miR132–p250GAP pathway plays a key role in activity-dependent structural and functional plasticity.

Footnotes

^‡To whom correspondence may be addressed. E-mail: waymang{at}ohsu.edu, goodmanr{at}ohsu.edu, or impeys{at}ohsu.edu
Author contributions: G.A.W., M.D., H.A., D.F., K.O., T.R.S., R.H.G., and S.I. designed research; G.A.W., M.D., H.A., D.F., O.V., H.-Y.M.C., D.M., and S.I. performed research; G.A.W., M.D., H.A., D.F., O.V., H.-Y.M.C., D.M., K.O., and S.I. analyzed data; and G.A.W., H.A., D.F., D.M., K.O., T.R.S., R.H.G., and S.I. wrote the paper.
The authors declare no conflict of interest.
This article contains supporting information online at www.pnas.org/cgi/content/full/0803072105/DCSupplemental.