An activity-induced microRNA controls dendritic spine formation by regulating Rac1-PAK signaling.
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 synaptic plasticity remain largely uncharacterized. We show here that the CREB- and activity-regulated microRNA, miR132, is induced during periods of active synaptogenesis. Moreover, miR132 is necessary and sufficient for hippocampal spine formation. Expression of the miR132 target, p250GAP, is inversely correlated with miR132 levels and spinogenesis. Furthermore, knockdown of p250GAP increases spine formation while introduction of a p250GAP mutant unresponsive to miR132 attenuates this activity. Inhibition of miR132 decreases both mEPSC frequency and the number of GluR1-positive spines, while knockdown of p250GAP has the opposite effect. Additionally, we show that the miR132/p250GAP circuit regulates Rac1 activity and spine formation by modulating synapse-specific Kalirin7-Rac1 signaling. These data suggest that neuronal activity regulates spine formation, in part, by increasing miR132 transcription, which in turn activates a Rac1-Pak actin remodeling pathway.
Oregon Stem Cell Center, Oregon Health and Science University, Portland, OR, USA. impeys@ohsu.edu
Soren
S
Impey
Monika
M
Davare
Adam
A
Lesiak
Adam
A
Lasiek
Dale
D
Fortin
Hideaki
H
Ando
Olga
O
Varlamova
Karl
K
Obrietan
Thomas R
TR
Soderling
Richard H
RH
Goodman
Gary A
GA
Wayman
D000818:Animals; D001640:Bicuculline / Q000378:metabolism; D002478:Cells, Cultured; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D049229:Dendritic Spines / Q000502:physiology* / Q000648:ultrastructure; D018756:GABA Antagonists / Q000378:metabolism; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000502:physiology*; D013569:Synapses / Q000502:physiology*; D054462:p21-Activated Kinases / Q000235:genetics / Q000378:metabolism*; D020830:rac1 GTP-Binding Protein / Q000235:genetics / Q000378:metabolism*
D017362:Cyclic AMP Response Element-Binding Protein; D018756:GABA Antagonists; D020662:Guanine Nucleotide Exchange Factors; C102365:Kalrn protein, rat; C548821:MIRN132 microRNA, rat; D035683:MicroRNAs; D054462:p21-Activated Kinases; D020830:rac1 GTP-Binding Protein; D001640:Bicuculline