Conditional knockout of Mir218-2 in INs, but not PNs, is sufficient to recapitulate long-term instability. 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. Changes in gene expression in the absence of miR-218 suggest that network assembly is impaired. Early life inhibition of miR-218 results in an adult brain with a predisposition to seizures. MiR-218 is highly expressed in the hippocampus and enriched in both excitatory principal neurons (PNs) and GABAergic inhibitory interneurons (INs). Here, we identified miR-218 as a critical regulator of hippocampal assembly. However, the mechanisms used by miRNAs to instruct brain development remain largely unexplored. Indeed, deletion of neuron-enriched miRNAs induces strong developmental phenotypes, and miRNA levels are altered in patients with neurodevelopmental disorders. Post-transcriptional regulation by microRNAs (miRNAs) is a key aspect of this program. The assembly of the mammalian brain is orchestrated by temporally coordinated waves of gene expression.
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