Article

Loss of microRNAs in pyramidal neurons leads to specific changes in inhibitory synaptic transmission in the prefrontal cortex.

Departments of Ophthalmology and Physiology, University of California, San Francisco, CA 94143, USA.
Molecular and Cellular Neuroscience (impact factor: 3.66). 06/2012; 50(3-4):283-92. DOI:10.1016/j.mcn.2012.06.002 pp.283-92
Source: PubMed

ABSTRACT MicroRNAs (miRNAs) are critical regulators of nervous system function, and in vivo knockout studies have demonstrated that miRNAs are necessary for multiple aspects of neuronal development and survival. However, the role of miRNA biogenesis in the formation and function of synapses in the cerebral cortex is only minimally understood. Here, we have generated and characterized a mouse line with a conditional neuronal deletion of Dgcr8, a miRNA biogenesis protein predicted to process miRNAs exclusively. Loss of Dgcr8 in pyramidal neurons of the cortex results in a non-cell-autonomous reduction in parvalbumin interneurons in the prefrontal cortex, accompanied by a severe deficit in inhibitory synaptic transmission and a corresponding reduction of inhibitory synapses. Together, these results suggest a vital role for miRNAs in governing essential aspects of inhibitory transmission and interneuron development in the mammalian nervous system. These results may be relevant to human diseases such as schizophrenia, where both altered Dgcr8 levels as well as aberrant inhibitory transmission in the prefrontal cortex have been postulated to contribute to the pathophysiology of the disease.

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    Article: miRNA Regulons Associated with Synaptic Function
    Maria Paschou, Maria D. Paraskevopoulou, Ioannis S. Vlachos, Pelagia Koukouraki, Artemis G. Hatzigeorgiou, Epaminondas Doxakis
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    ABSTRACT: Differential RNA localization and local protein synthesis regulate synapse function and plasticity in neurons. MicroRNAs are a conserved class of regulatory RNAs that control mRNA stability and translation in tissues. They are abundant in the brain but the extent into which they are involved in synaptic mRNA regulation is poorly known. Herein, a computational analysis of the coding and 3′UTR regions of 242 presynaptic and 304 postsynaptic proteins revealed that 91% of them are predicted to be microRNA targets. Analysis of the longest 3′UTR isoform of synaptic transcripts showed that presynaptic mRNAs have significantly longer 3′UTR than control and postsynaptic mRNAs. In contrast, the shortest 3′UTR isoform of postsynaptic mRNAs is significantly shorter than control and presynaptic mRNAs, indicating they avert microRNA regulation under specific conditions. Examination of microRNA binding site density of synaptic 3′UTRs revealed that they are twice as dense as the rest of protein-coding transcripts and that approximately 50% of synaptic transcripts are predicted to have more than five different microRNA sites. An interaction map exploring the association of microRNAs and their targets revealed that a small set of ten microRNAs is predicted to regulate 77% and 80% of presynaptic and postsynaptic transcripts, respectively. Intriguingly, many of these microRNAs have yet to be identified outside primate mammals, implicating them in cognition differences observed between high-level primates and non-primate mammals. Importantly, the identified miRNAs have been previously associated with psychotic disorders that are characterized by neural circuitry dysfunction, such as schizophrenia. Finally, molecular dissection of their KEGG pathways showed enrichment for neuronal and synaptic processes. Adding on current knowledge, this investigation revealed the extent of miRNA regulation at the synapse and predicted critical microRNAs that would aid future research on the control of neuronal plasticity and etiology of psychiatric diseases.
    PLoS ONE 10/2012; 7(10):e46189. · 4.09 Impact Factor
Data provided are for informational purposes only. Although carefully collected, accuracy cannot be guaranteed. The impact factor represents a rough estimation of the journal's impact factor and does not reflect the actual current impact factor. Publisher conditions are provided by RoMEO. Differing provisions from the publisher's actual policy or licence agreement may be applicable.

Keywords

aberrant inhibitory transmission
 
conditional neuronal deletion
 
corresponding reduction
 
cortex results
 
Dgcr8 levels
 
essential aspects
 
human diseases
 
inhibitory synapses
 
inhibitory synaptic transmission
 
mammalian nervous system
 
miRNA biogenesis protein
 
miRNAs
 
multiple aspects
 
nervous system function
 
non-cell-autonomous reduction
 
parvalbumin interneurons
 
process miRNAs
 
pyramidal neurons
 
vital role
 
vivo knockout studies