title: MicroRNA-101 Regulates Multiple Developmental Programs to Constrain Excitation in Adult Neural Networks.
abstract: A critical feature of neural networks is that they balance excitation and inhibition to prevent pathological dysfunction. How this is achieved is largely unknown, although deficits in the balance contribute to many neurological disorders. We show here that a microRNA (miR-101) is a key orchestrator of this essential feature, shaping the developing network to constrain excitation in the adult. Transient early blockade of miR-101 induces long-lasting hyper-excitability and persistent memory deficits. Using target site blockers in vivo, we identify multiple developmental programs regulated in parallel by miR-101 to achieve balanced networks. Repression of one target, NKCC1, initiates the switch in γ-aminobutyric acid (GABA) signaling, limits early spontaneous activity, and constrains dendritic growth. Kif1a and Ank2 are targeted to prevent excessive synapse formation. Simultaneous de-repression of these three targets completely phenocopies major dysfunctions produced by miR-101 blockade. Our results provide new mechanistic insight into brain development and suggest novel candidates for therapeutic intervention.
authors.affiliation: Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, USA. Electronic address: glippi@ucsd.edu.
authors.forename: Giordano
authors.initials: G
authors.lastname: Lippi
authors.affiliation: Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Catarina C
authors.initials: CC
authors.lastname: Fernandes
authors.affiliation: Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Laura A
authors.initials: LA
authors.lastname: Ewell
authors.affiliation: Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Danielle
authors.initials: D
authors.lastname: John
authors.affiliation: Department of Biomedical, Metabolic, and Neural Sciences, Center for Neuroscience and Neurotechnology, University of Modena and Reggio Emilia, Modena 41125, Italy.
authors.forename: Benedetto
authors.initials: B
authors.lastname: Romoli
authors.affiliation: Department of Biomedical, Metabolic, and Neural Sciences, Center for Neuroscience and Neurotechnology, University of Modena and Reggio Emilia, Modena 41125, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Curia
authors.affiliation: Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Seth R
authors.initials: SR
authors.lastname: Taylor
authors.affiliation: Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: E Paxon
authors.initials: EP
authors.lastname: Frady
authors.affiliation: Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Anne B
authors.initials: AB
authors.lastname: Jensen
authors.affiliation: Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Jerry C
authors.initials: JC
authors.lastname: Liu
authors.affiliation: Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Melanie M
authors.initials: MM
authors.lastname: Chaabane
authors.affiliation: Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Cherine
authors.initials: C
authors.lastname: Belal
authors.affiliation: Institute for Genomic Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Jason L
authors.initials: JL
authors.lastname: Nathanson
authors.affiliation: Department of Biomedical, Metabolic, and Neural Sciences, Center for Neuroscience and Neurotechnology, University of Modena and Reggio Emilia, Modena 41125, Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: Zoli
authors.affiliation: Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, USA; Center for Neural Circuits and Behavior, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Jill K
authors.initials: JK
authors.lastname: Leutgeb
authors.affiliation: Department of Biomedical, Metabolic, and Neural Sciences, Center for Neuroscience and Neurotechnology, University of Modena and Reggio Emilia, Modena 41125, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Biagini
authors.affiliation: Institute for Genomic Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Gene W
authors.initials: GW
authors.lastname: Yeo
authors.affiliation: Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, USA. Electronic address: dberg@ucsd.edu.
authors.forename: Darwin K
authors.initials: DK
authors.lastname: Berg
mesh_terms: D000818:Animals; D017487:Ankyrins / Q000235:genetics / Q000378:metabolism; D001522:Behavior, Animal; D001921:Brain / Q000254:growth & development / Q000378:metabolism*; D003712:Dendrites; D018507:Gene Expression Regulation, Developmental / Q000235:genetics*; D016547:Kinesins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D009415:Nerve Net / Q000254:growth & development / Q000378:metabolism; D009434:Neural Pathways / Q000254:growth & development / Q000378:metabolism; D018408:Patch-Clamp Techniques; D016133:Polymerase Chain Reaction; D017423:Sequence Analysis, RNA; D064506:Solute Carrier Family 12, Member 2 / Q000235:genetics / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: C498995:Ank2 protein, mouse; D017487:Ankyrins; C490576:Kif1a protein, mouse; C581233:MIRN101 microRNA, mouse; D035683:MicroRNAs; C578878:Slc12a2 protein, mouse; D064506:Solute Carrier Family 12, Member 2; D005680:gamma-Aminobutyric Acid; D016547:Kinesins
keywords: GABA switch; NKCC1; excitation/inhibition (E/I); hyper-excitability; miR-101; microRNA; network development; neurodevelopmental disorders; synaptogenesis; target-site blockers