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 invivo, 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.
Highlights
Balanced excitation is a critical feature of properly functioning neural circuits
MiR-101 Is a Potential Master Regulator of Network Formation To identify miRNAs orchestrating the complex series of events occurring during network formation, we performed small RNA sequencing of the mouse hippocampus on postnatal day 12 (P12)
The hippocampus was chosen because of its known function and well defined circuitry; P12 was chosen because it is within a critical developmental window (Liu et al, 2006)
Summary
Balanced excitation is a critical feature of properly functioning neural circuits. Aberrant activity is characteristic of numerous neurological disorders, including autism spectrum disorder (ASD), Rett syndrome, schizophrenia, and epilepsy (Belforte et al, 2010; Chao et al, 2010; Dzhala et al, 2005; Rubenstein and Merzenich, 2003; Yizhar et al, 2011; Zoghbi and Bear, 2012). Formative events in the first few weeks of post-natal life specify the ratio of excitatory and inhibitory input (E/I) and determine the excitability of neural circuits for the adult (Ben-Ari, 2002; Blankenship and Feller, 2010). During this time, the developing nervous system transitions from an initial period of rapid growth and exuberant synapse formation to a period during which circuits undergo refinement and consolidation (Blankenship and Feller, 2010; Kirkby et al, 2013). How this complex process of network construction is guided to ensure proper excitation is largely unknown
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