MicroRNA-218 instructs proper assembly of hippocampal networks
Seth R Taylor,
Mariko Kobayashi,
Antonietta Vilella,
Durgesh Tiwari,
Norjin Zolboot,
Jessica X Du,
Kathryn R Spencer,
Andrea Hartzell,
Carol Girgiss,
Yusuf T Abaci,
Yufeng Shao,
Claudia De Sanctis,
Gian Carlo Bellenchi,
Robert B Darnell,
Christina Gross,
Michele Zoli,
Darwin K Berg,
Giordano Lippi
Affiliations
Seth R Taylor
Division of Biological Sciences, University of California, San Diego, La Jolla, United States
Mariko Kobayashi
Laboratory of Molecular Neuro-oncology, Howard Hughes Medical Institute, Rockefeller University, New York, United States
Antonietta Vilella
Department of Biomedical, Metabolic and Neural Sciences; Center for Neuroscience and Neurotechnology (CfNN), University of Modena and Reggio Emilia, Modena, Italy
Durgesh Tiwari
Division of Neurology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, United States; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, United States
Norjin Zolboot
Department of Neuroscience, Scripps Research Institute, La Jolla, United States
Jessica X Du
Department of Neuroscience, Scripps Research Institute, La Jolla, United States
Kathryn R Spencer
Department of Neuroscience, Scripps Research Institute, La Jolla, United States
Andrea Hartzell
Department of Neuroscience, Scripps Research Institute, La Jolla, United States
Carol Girgiss
Division of Biological Sciences, University of California, San Diego, La Jolla, United States
Yusuf T Abaci
Division of Biological Sciences, University of California, San Diego, La Jolla, United States
Yufeng Shao
Department of Neuroscience, Scripps Research Institute, La Jolla, United States
Claudia De Sanctis
Institute of Genetics and Biophysics A Buzzati-Traverso, Naples, Italy
Gian Carlo Bellenchi
Institute of Genetics and Biophysics A Buzzati-Traverso, Naples, Italy; IRCCS Fondazione Santa Lucia, Rome, Italy
Division of Neurology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, United States; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, United States
Michele Zoli
Department of Biomedical, Metabolic and Neural Sciences; Center for Neuroscience and Neurotechnology (CfNN), University of Modena and Reggio Emilia, Modena, Italy
Darwin K Berg
Division of Biological Sciences, University of California, San Diego, La Jolla, United States
The assembly of the mammalian brain is orchestrated by temporally coordinated waves of gene expression. Post-transcriptional regulation by microRNAs (miRNAs) is a key aspect of this program. Indeed, deletion of neuron-enriched miRNAs induces strong developmental phenotypes, and miRNA levels are altered in patients with neurodevelopmental disorders. However, the mechanisms used by miRNAs to instruct brain development remain largely unexplored. Here, we identified miR-218 as a critical regulator of hippocampal assembly. MiR-218 is highly expressed in the hippocampus and enriched in both excitatory principal neurons (PNs) and GABAergic inhibitory interneurons (INs). Early life inhibition of miR-218 results in an adult brain with a predisposition to seizures. Changes in gene expression in the absence of miR-218 suggest that network assembly is impaired. Indeed, we find that miR-218 inhibition results in the disruption of early depolarizing GABAergic signaling, structural defects in dendritic spines, and altered intrinsic membrane excitability. Conditional knockout of Mir218-2 in INs, but not PNs, is sufficient to recapitulate long-term instability. Finally, de-repressing Kif21b and Syt13, two miR-218 targets, phenocopies the effects on early synchronous network activity induced by miR-218 inhibition. Taken together, the data suggest that miR-218 orchestrates formative events in PNs and INs to produce stable networks.
