MicroRNA-101 Regulates Multiple Developmental Programs to Constrain Excitation in Adult Neural Networks

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. •MiR-101 orchestrates early network development to limit excitation in the adult•Transient miR-101 blockade leads to hyper-excitability and memory deficits•MiR-101 targets NKCC1 to facilitate the GABA switch and constrains dendrites•Ank2 and Kif1a are targeted by miR-101 to limit formation of excitatory synapses Lippi et al. discovered that microRNA-101 regulates multiple genetic programs in parallel to orchestrate a major transition in early development, ensuring that adult neural circuits display appropriate excitability. MicroRNA-101 blockade induces hyper-excitability and memory deficits characteristic of numerous neurodevelopmental disorders.