title: 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.
authors.affiliation: Instituto de Neurociencias (Universidad Miguel Hernández-Consejo Superior de Investigaciones Científicas), Av. Santiago Ramón y Cajal s/n., 03550 Sant Joan d'Alacant, Alicante, Spain.
authors.forename: Anna
authors.initials: A
authors.lastname: Fiorenza
authors.affiliation: Instituto de Neurociencias (Universidad Miguel Hernández-Consejo Superior de Investigaciones Científicas), Av. Santiago Ramón y Cajal s/n., 03550 Sant Joan d'Alacant, Alicante, Spain.
authors.forename: Jose P
authors.initials: JP
authors.lastname: Lopez-Atalaya
authors.affiliation: Instituto de Neurociencias (Universidad Miguel Hernández-Consejo Superior de Investigaciones Científicas), Av. Santiago Ramón y Cajal s/n., 03550 Sant Joan d'Alacant, Alicante, Spain.
authors.forename: Victor
authors.initials: V
authors.lastname: Rovira
authors.affiliation: Instituto de Neurociencias (Universidad Miguel Hernández-Consejo Superior de Investigaciones Científicas), Av. Santiago Ramón y Cajal s/n., 03550 Sant Joan d'Alacant, Alicante, Spain.
authors.forename: Marilyn
authors.initials: M
authors.lastname: Scandaglia
authors.affiliation: Instituto de Neurociencias (Universidad Miguel Hernández-Consejo Superior de Investigaciones Científicas), Av. Santiago Ramón y Cajal s/n., 03550 Sant Joan d'Alacant, Alicante, Spain.
authors.forename: Emilio
authors.initials: E
authors.lastname: Geijo-Barrientos
authors.affiliation: Instituto de Neurociencias (Universidad Miguel Hernández-Consejo Superior de Investigaciones Científicas), Av. Santiago Ramón y Cajal s/n., 03550 Sant Joan d'Alacant, Alicante, Spain.
authors.forename: Angel
authors.initials: A
authors.lastname: Barco
mesh_terms: D000200:Action Potentials / Q000235:genetics; D000818:Animals; D056547:CA1 Region, Hippocampal / Q000378:metabolism / Q000503:physiopathology; D003214:Conditioning, Classical; D053487:DEAD-box RNA Helicases / Q000235:genetics*; D005239:Fear / Q000502:physiology; D005260:Female; D006963:Hyperphagia / Q000235:genetics / Q000378:metabolism; D007608:Kainic Acid / Q000008:administration & dosage; D008297:Male; D008568:Memory / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D035683:MicroRNAs / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D009473:Neuronal Plasticity; D009474:Neurons / Q000378:metabolism / Q000502:physiology*; D010641:Phenotype; D016548:Prosencephalon / Q000378:metabolism / Q000503:physiopathology*; D043244:Ribonuclease III / Q000235:genetics*; D012640:Seizures / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism*; D017423:Sequence Analysis, RNA
chemical_list: D035683:MicroRNAs; C509781:Dicer1 protein, mouse; D043244:Ribonuclease III; D053487:DEAD-box RNA Helicases; D007608:Kainic Acid
keywords: Dicer; activity-driven transcription; epilepsy; learning and memory; miRNAs; neuronal excitability; neuronal homeostasis; obesity; regulation of gene expression