Synaptic remodeling in response to neuronal activity relies on activity-stimulated changes in gene expression, and a new study shows that the regulatory microRNA miR132 is a key player in this pathway. In a report due out this week in PNAS, Soren Impey and Richard Goodman at Oregon Health Sciences University in Portland, Oregon, present evidence that induction of miR132 contributes to dendrite growth after neuronal stimulation via downregulation of the synaptic protein p250GAP.

In the study, first author Gary Wayman and colleagues show that miR132 rises rapidly in hippocampal neurons after synaptic stimulation. Their data indicate that activation of the transcription factor CREB increases miR132 expression, resulting in enhanced dendrite growth. The effect of miR132 on dendrite plasticity is mediated in part by translational repression of the Rho family GTPase activating protein, p250GAP, which is associated with NMDA receptors and regulates dendritic remodeling via the Rac GTPase.

Regulatory microRNAs have been implicated in pathways related to Alzheimer disease, where they can modulate expression of the β-secretase enzyme (see ARF related news story and ARF news story), and in Parkinson disease, where they control dopamine neuron development (see ARF related news story). Along with a recent report linking another microRNA to plasticity at neuromuscular synapses (Simon et al., 2008), the new study adds to a sense that we have glimpsed only the tip of the iceberg when it comes to the roles of microRNA in neuronal function.—Pat McCaffrey.

Reference:
Wayman GA, Davare M, Ando H, Fortin D, Varlamova O, Cheng HM, Marks D, Obrietan K, Soderling TR Goodman RH, Impey S. An activity-regulated microRNA controls dendritic plasticity by downregulating p250GAP. 2008 June 16. PNAS Early Edition. Abstract

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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:

    . Conditional loss of Dicer disrupts cellular and tissue morphogenesis in the cortex and hippocampus. J Neurosci. 2008 Apr 23;28(17):4322-30. PubMed.

    . Molecular biology. miRNAs in neurodegeneration. Science. 2007 Aug 31;317(5842):1179-80. PubMed.

    . 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. PubMed.

    . 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.

    . Cerebellar neurodegeneration in the absence of microRNAs. J Exp Med. 2007 Jul 9;204(7):1553-8. PubMed.

    . A brain-specific microRNA regulates dendritic spine development. Nature. 2006 Jan 19;439(7074):283-9. PubMed.

    . 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.

References

News Citations

  1. BACE in Alzheimer’s—Does MicroRNA Control Translation?
  2. Number 107: MicroRNA Gets to First BACE in AD Brain
  3. Research Brief: Do MicroRNAs Cause Parkinson Disease?

Paper Citations

  1. . The microRNA miR-1 regulates a MEF-2-dependent retrograde signal at neuromuscular junctions. Cell. 2008 May 30;133(5):903-15. PubMed.
  2. . 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.

Further Reading

Papers

  1. . Regulation of dendritic spine morphology by an NMDA receptor-associated Rho GTPase-activating protein, p250GAP. J Neurochem. 2008 May;105(4):1384-93. PubMed.
  2. . 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.

Primary Papers

  1. . 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.