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

Abstract

SUMMARY A critical feature of neural networks is that they balance excitation and inhibition to prevent pathological dysfunction. How this is achieved is largely unknown, though 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 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.

MicroRNAs in neural development: from master regulators to fine-tuners

“…In a more recent study, the transient inhibition of miR-101 using antagomirs induced dendritic growth in the CA1 and CA3 region of the hippocampus by repressing the sodium transporter NKCC1 (SLC12A2). Intriguingly, this transient inhibition of specific miRNAs such as miR-101 in young mice was sufficient to cause cognitive impairments in adulthood (Lippi et al, 2016). Therefore, this study provides evidence that miRNA-dependent control of neuronal morphogenesis during developmental stages has an important impact on the function of neural circuits and cognitive abilities in the adult.…”

“…Transient inhibition of miR-101 activity by antagomir injection into the dorsal hippocampus of mice soon after birth was shown to change the balance between excitatory and inhibitory synaptic transmission (E/I balance) in adult animals (Lippi et al, 2016). This study also elegantly showed that a single miRNA can simultaneously regulate pre-and postsynaptic development by suppressing different sets of targets.…”

Neurotransmitter Switching Regulated by miRNAs Controls Changes in Social Preference

“…A TSB selectively protects the MRE on a specific mRNA by stopping a given miR from binding and repressing its expression, leaving all other mRNA targets unaffected (Lippi et al, 2016) (Figures 6A and 6B, third oligonucleotide pair). Local delivery to the AOB of the TSB protecting the miR-375 MRE on Pax6 (Pax6-375-TSB) increased Pax6 mRNA levels comparable to those achieved with a.375 (Figures 6F and 6G).…”

Novel therapeutic approaches for disease-modification of epileptogenesis for curing epilepsy

“…Indeed, a number of groups have identified pro-inflammatory and/or pro-epileptogenic miRNAs, such as miR-155 [241] and miR-134 [242]. Emerging evidence on these and other miRNAs point to a potential role in mediating epileptogenesis [243,244,245], with some studies demonstrating long-lasting pro-excitatory effects from even transient miRNA blockade, as Lippi et al did with miR-101 [246]. Antagomirs, mi-RNA-silencing oligonucleotides, represent a potentially viable route for disease-intervention or modulation, as they have the capability to potently inhibiting specific miRNAs.…”