microRNAs are a class of small non-coding RNA molecules negatively regulating gene expression at post-transcriptional level in many tissues including the central nervous system. cAMP response element binding protein (CREB) is a key nuclear factor highly expressed in hippocampal neurons on which many signal pathways converge. Recent studies have found that microRNA-181a is rich in mature nerve cells, and bioinformatics analysis shows that the CREB1 mRNA 3'-untranslated region (3'UTR) contains complementary sequence to the miR-181a seed region. In this study, we investigated whether miR-181a is a negative regulator for CREB1 expression in neurons. It was found that the expression of miR-181a was negatively correlated with Insulin-like growth factor-1 (IGF-1) and CREB1 in the Lewis rat hippocampus. miR-181a bound to CREB1 mRNA through a specific binding site in the 3'UTR sequence. The expression of CREB1 in PC12 cells was down-regulated by transfection with a miR-181a mimic and up-regulated by a miR-181a inhibitor. A down-regulated miR-181a and an up-regulated CREB1 were observed in IGF-1-stimulated PC12 cells. And miR-181a inhibited dendritic growth of cultured hippocampus neurons. These suggest that miR-181a is involved in IGF-1-regulated CREB1 expression by targeting its mRNA 3'UTR. microRNAs (miRNAs) regulate gene expression at the post-transcriptional level and are involved in the central nervous system development. Here, we demonstrate that miR-181a can inhibit the expression of the transcription factor CREB1 by specifically targeting its mRNA 3'UTR and inhibit the development of hippocampus neurons. Repressed expression of miR-181a is involved in IGF-1-mediated up-regulation of CREB1 in vivo and in vitro. These findings indicate that miR-181a could be a potential target for preventing neurodegenerative diseases.