Wayman GA, Davare M, Ando H, Fortin D, Varlamova O, Cheng HY, Marks D, Obrietan K, Soderling TR, Goodman RH, Impey S. An activity-regulated microRNA controls dendritic plasticity by down-regulating p250GAP. Proc Natl Acad Sci U S A. 2008 Jul 1;105(26):9093-8. PubMed.

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  1. It’s fascinating to see that microRNAs are slowly but surely making their mark in neurobiology. This is very nice work by Gary Wayman and colleagues, further characterizing a novel signaling pathway implicating miR-132 in neuronal function (Vo et al., 2005). The current work is in line with previous studies demonstrating a role for specific microRNAs in synaptic development/plasticity (miR-134) and neuronal identity (miR-124) (Makeyev et al., 2007; Schratt et al., 2006).

    Here, the authors show that bicuculline, a compound that increases spontaneous synaptic activity and dendritic outgrowth in cultured neurons, induces miR-132 expression. This effect is dependent on the transcription factor CREB and implicates p250GAP as a downstream effector target of miR-132. Overall, they elegantly show that miR-132 is necessary for the bicuculline-induced effects on dendritic growth in hippocampal neurons.

    Along with the above-mentioned studies, this work supports the interesting possibility that dysregulation of microRNA pathways could contribute to a neurodegenerative (Hébert and De Strooper, 2007; Hébert et al., 2008) or psychiatric phenotype in humans (note that bicuculline is commonly used to study epilepsy). It has been known for a long time that synaptic dysfunction is tightly related to Alzheimer disease, for example. Thus, changes in this and possibly other signaling pathways may have profound effects on memory and AD pathology.

    While progressive neuronal loss is observed in post-mitotic neurons (including hippocampal neurons) of miRNA-deficient mice (Davis et al., 2008; Schaefer et al., 2007), it would be interesting to assess the biological role of miR-132, among others, in an in vivo context, either by gene knockout or by RNA knockdown.

    References:

    Davis TH, Cuellar TL, Koch SM, Barker AJ, Harfe BD, McManus MT, Ullian EM. Conditional loss of Dicer disrupts cellular and tissue morphogenesis in the cortex and hippocampus. J Neurosci. 2008 Apr 23;28(17):4322-30. PubMed.

    Hébert SS, De Strooper B. Molecular biology. miRNAs in neurodegeneration. Science. 2007 Aug 31;317(5842):1179-80. PubMed.

    Hébert SS, Horré K, Nicolaï L, Papadopoulou AS, Mandemakers W, Silahtaroglu AN, Kauppinen S, Delacourte A, De Strooper B. Loss of microRNA cluster miR-29a/b-1 in sporadic Alzheimer's disease correlates with increased BACE1/beta-secretase expression. Proc Natl Acad Sci U S A. 2008 Apr 29;105(17):6415-20. Epub 2008 Apr 23 PubMed.

    Makeyev EV, Zhang J, Carrasco MA, Maniatis T. The MicroRNA miR-124 promotes neuronal differentiation by triggering brain-specific alternative pre-mRNA splicing. Mol Cell. 2007 Aug 3;27(3):435-48. PubMed.

    Schaefer A, O'Carroll D, Tan CL, Hillman D, Sugimori M, Llinas R, Greengard P. Cerebellar neurodegeneration in the absence of microRNAs. J Exp Med. 2007 Jul 9;204(7):1553-8. PubMed.

    Schratt GM, Tuebing F, Nigh EA, Kane CG, Sabatini ME, Kiebler M, Greenberg ME. A brain-specific microRNA regulates dendritic spine development. Nature. 2006 Jan 19;439(7074):283-9. PubMed.

    Vo N, Klein ME, Varlamova O, Keller DM, Yamamoto T, Goodman RH, Impey S. A cAMP-response element binding protein-induced microRNA regulates neuronal morphogenesis. Proc Natl Acad Sci U S A. 2005 Nov 8;102(45):16426-31. PubMed.

    View all comments by Sébastien S. Hébert

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