Oregon Stem Cell Center, Oregon Health and Science University, Portland, OR, USA.
Mol Cell Neurosci. 2010 Jan;43(1):146-56. doi: 10.1016/j.mcn.2009.10.005. Epub 2009 Oct 20.
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.
活性调节基因表达被认为在神经元回路的发育和精细化中起着关键作用。然而，调节突触可塑性的转录网络在很大程度上仍未被描述。我们在这里表明，CREB 和活性调节 microRNA，miR132，在活跃的突触发生期间被诱导。此外，miR132 对于海马体棘突形成是必要和充分的。miR132 靶标 p250GAP 的表达与 miR132 水平和棘突发生呈负相关。此外，p250GAP 的敲低增加了棘突形成，而对 miR132 无反应的 p250GAP 突变体的引入则减弱了这种活性。miR132 的抑制降低了 mEPSC 的频率和 GluR1 阳性棘突的数量，而 p250GAP 的敲低则产生相反的效果。此外，我们表明，miR132/p250GAP 电路通过调节突触特异性 Kalirin7-Rac1 信号来调节 Rac1 活性和棘突形成。这些数据表明，神经元活性通过增加 miR132 转录来调节棘突形成，从而激活 Rac1-Pak 肌动蛋白重塑途径。
