Cerebellar tonic inhibition orchestrates the maturation of information processing and motor coordination

Tonic inhibition in cerebellar granule cells (GC) is crucial in information coding fidelity for motor coordination. It emerges in activity-dependent and-independent manners, and their interplay evolves with age. However, specific molecular and cellular mechanisms and how their change affects network-level computation and motor behavior remain unclear. Here we show that, while net tonic inhibitory current remains unchanged, the main source of tonic GABA switches from synaptic spillover (neuronal activity-dependent) to astrocytic Best1 (activity-independent) throughout adolescence (4-8 weeks) in mice. Computational modeling based on experimental data demonstrated that this switch down-regulates the internally generated network activity mediating mutual inhibition between GC clusters receiving different inputs, thereby enhancing their independence. Consistent with simulations, 3D-posture analysis revealed an age-dependent increase in independent limb movements during spontaneous motion, which was impaired in Best1 knockout mice. Our findings highlight the late-stage development of complex motor coordination driven by the emergence of astrocyte-mediated tonic inhibition. O_LI6 main figures, 58 references, 5,924 words in the manuscript (excluding the abstract, tables, figure legends and references). C_LIO_LISupplementary information: 1 text (supplementary methods), 9 figures, 4 movies, and 1 table. C_LI