Cerebellar microRNA-206 tunes Purkinje neuron firing dynamics to control sensorimotor gating

MicroRNAs are potent regulators of gene expression in the brain, yet the cellular mechanisms through which they shape neuronal activity and behavior remain poorly understood. MicroRNA-206 (miR-206) has been genetically and transcriptionally linked to schizophrenia and other neuropsychiatric disorders, but its functions in the nervous system are largely unknown. Here we show that miR-206 expression in the brain is restricted to postnatal cerebellar Purkinje cells (PCs). miR-206 was dispensable for PC cell fate specification, dendritic morphogenesis, and cerebellar-regulated motor coordination. Transcriptional profiling with single-nucleus and spatial resolution, integrated with Ago2-associated miRNA-target repression mapping (HITS-CLIP) and ribosome-associated RNA profiling (TRAP-seq), showed that miR-206 regulates translational programs in PCs controlling neuronal excitability. Accordingly, miR-206 deficiency increased the tonic firing of PCs, whereas elevating miR-206 expression shifted PCs from tonic to high-frequency burst firing. Constitutive or PC-specific deletion of miR-206 impaired prepulse inhibition (PPI) of the acoustic startle response, a conserved form of sensorimotor gating disrupted in schizophrenia and related disorders. Restoration of miR-206 expression in PCs rescued PPI deficits in miR-206-deficient mice, while elevating miR-206 expression in PCs impaired PPI in wild-type animals. Together, these findings reveal that a schizophrenia-linked microRNA tunes Purkinje neuron firing dynamics to control sensorimotor gating.