Blocking miRNA Biogenesis in Adult Forebrain Neurons Enhances Seizure Susceptibility, Fear Memory, and Food Intake by Increasing Neuronal Responsiveness

Abstract

The RNase Dicer is essential for the maturation of most microRNAs, a molecular system that plays an essential role in fine-tuning gene expression. To gain molecular insight into the role of Dicer and the microRNA system in brain function, we conducted 2 complementary RNA-seq screens in the hippocampus of inducible forebrain-restricted Dicer1 mutants aimed at identifying the microRNAs primarily affected by Dicer loss and their targets, respectively. Functional genomics analyses predicted the main biological processes and phenotypes associated with impaired microRNA maturation, including categories related to microRNA biology, signal transduction, seizures, and synaptic transmission and plasticity. Consistent with these predictions, we found that, soon after recombination, Dicer-deficient mice exhibited an exaggerated seizure response, enhanced induction of immediate early genes in response to different stimuli, stronger and more stable fear memory, hyperphagia, and increased excitability of CA1 pyramidal neurons. In the long term, we also observed slow and progressive excitotoxic neurodegeneration. Overall, our results indicate that interfering with microRNA biogenesis causes an increase in neuronal responsiveness and disrupts homeostatic mechanisms that protect the neuron against overactivation, which may explain both the initial and late phenotypes associated with the loss of Dicer in excitatory neurons.

Klf4 inhibits tumor growth and metastasis by targeting microRNA-31 in human hepatocellular carcinoma

“…miRNAs are post-transcription regulators of many genes, and their deregulation is related to cancer initiation, development and progression (33). Proliferation and metastasis, two hallmarks of malignancy, are the leading causes for cancer-related death (34).…”

Loss of Kdm5c Causes Spurious Transcription and Prevents the Fine-Tuning of Activity-Regulated Enhancers in Neurons

“…Each independent sample was assayed in duplicate and normalized using GAPDH levels. RNA preparation for sequencing was performed as described in (Fiorenza et al, 2016). Information on library preparation and size, mapping to reference genome and differential expression and functional genomics analyses can be found in Supplemental Experimental Procedures.…”

miRNAs in synapse development and synaptic plasticity

“…In Ncoa3 knockdown neurons which have a low RISC activity, dendrites become more complex and bear smaller dendritic spines [27]. Deletion of Dicer1 in the adult mouse forebrain shifts dendritic arborization towards distal dendrites and elongates dendritic spines [25]. Specific miRNAs involved in neuronal morphogenesis have begun to be recognized.…”

“…This is first demonstrated in conditional Dicer1 knockout mice which have massive miRNA loss in forebrain excitatory neurons. These mice exhibit enhanced hippocampus-dependent spatial memory in the Morris water maze test and fear memory in the trace and the contextual fear conditioning test [25,26]. Since then, the importance of miRNAs in memory has been confirmed by experiments perturbing individual miRNAs.…”