MiR-132/212 Knockout Mice Reveal Roles for These miRNAs in Regulating Cortical Synaptic Transmission and Plasticity

Judit Remenyi,Andrew Macdonald,Bruno G Frenguelli,Yuriy Pankratov,Colin Mckenzie,Gyorgy Hutvagner,Oleg Palygin,Mirjam W M Van Den Bosch,J Simon C Arthur,Rajen B Mistry

doi:10.1371/journal.pone.0062509

Abstract

miR-132 and miR-212 are two closely related miRNAs encoded in the same intron of a small non-coding gene, which have been suggested to play roles in both immune and neuronal function. We describe here the generation and initial characterisation of a miR-132/212 double knockout mouse. These mice were viable and fertile with no overt adverse phenotype. Analysis of innate immune responses, including TLR-induced cytokine production and IFNβ induction in response to viral infection of primary fibroblasts did not reveal any phenotype in the knockouts. In contrast, the loss of miR-132 and miR-212, while not overtly affecting neuronal morphology, did affect synaptic function. In both hippocampal and neocortical slices miR-132/212 knockout reduced basal synaptic transmission, without affecting paired-pulse facilitation. Hippocampal long-term potentiation (LTP) induced by tetanic stimulation was not affected by miR-132/212 deletion, whilst theta burst LTP was enhanced. In contrast, neocortical theta burst-induced LTP was inhibited by loss of miR-132/212. Together these results indicate that miR-132 and/or miR-212 play a significant role in synaptic function, possibly by regulating the number of postsynaptic AMPA receptors under basal conditions and during activity-dependent synaptic plasticity.

Highlights

MiRNAs are small 20 to 22 base RNA species that are involved in the post transcriptional regulation of protein expression. miRNAs have been implicated in a wide range of processes ranging from cell proliferation and differentiation to the modulation of specific neuronal and immune function
In mammalian cells miRNAs typically interact with their target mRNAs via a 7 to 8 base seed sequence that is complementary to the target mRNA
In that study homozygous matings for the knockout resulted in a high rate of postnatal death that was attributed to a defect in mammary gland development in the knockout females [10]

Summary

Introduction

MiRNAs are small 20 to 22 base RNA species that are involved in the post transcriptional regulation of protein expression. miRNAs have been implicated in a wide range of processes ranging from cell proliferation and differentiation to the modulation of specific neuronal and immune function. In mammalian cells miRNAs typically interact with their target mRNAs via a 7 to 8 base seed sequence that is complementary to the target mRNA. This allows the miRNA to repress the expression of its targets either by inhibiting translation or promoting RNA degradation (reviewed in [1,2]). While it is clear that all 4 miRNA sequences are expressed from this locus, the expression level for miR-132 is much higher that for the other three miRNAs [3,9] This has led to the suggestion that miR-132 is the only functional miRNA expressed from this locus in neurons [9], this may not reflect the situation in all cell types

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Conclusion