Control of cerebellar granule cell output by sensory-evoked Golgi cell inhibition

Classical feed-forward inhibition involves an excitation–inhibition sequence that enhances the temporal precision of neuronal responses by narrowing the window for synaptic integration. In the input layer of the cerebellum, feed-forward inhibition is thought to preserve the temporal fidelity of granule cell spikes during mossy fiber stimulation. Although this classical feed-forward inhibitory circuit has been demonstrated in vitro, the extent to which inhibition shapes granule cell sensory responses in vivo remains unresolved. Here we combined whole-cell patch-clamp recordings in vivo and dynamic clamp recordings in vitro to directly assess the impact of Golgi cell inhibition on sensory information transmission in the granule cell layer of the cerebellum. We show that the majority of granule cells in Crus II of the cerebrocerebellum receive sensory-evoked phasic and spillover inhibition prior to mossy fiber excitation. This preceding inhibition reduces granule cell excitability and sensory-evoked spike precision, but enhances sensory response reproducibility across the granule cell population. Our findings suggest that neighboring granule cells and Golgi cells can receive segregated and functionally distinct mossy fiber inputs, enabling Golgi cells to regulate the size and reproducibility of sensory responses.Classical feed-forward inhibition (FFI) involves a sequence of excitation rapidly terminated by inhibition. This temporal sequence narrows the time window for synaptic integration and enforces precise spike timing (1–7). FFI is thought to be important for regulating the temporal fidelity of spike responses in many neural systems, including the motor system, where rapid and adaptable changes in muscle activity are essential for coordinated motor control (8–10). The cerebellum plays a central role in fine sculpting of movements, and damage to the cerebellum produces severe motor deficits, most notably enhanced temporal variability of voluntary movements (11, 12). These findings suggest that cerebellar circuits have the ability to preserve precise timing information during behavior (5, 6, 13), and in vitro studies have shown that feed-forward inhibitory networks in the input layer of the cerebellum provide a mechanism for maintaining the temporal fidelity of information transmission (6, 14, 15).Synaptic inhibition in the granule cell layer is generated by Golgi cells, GABAergic interneurons that provide direct inhibitory input to granule cells (6, 15–17). The prevailing view is that, when mossy fibers are activated, granule cells receive both monosynaptic excitation and disynaptic FFI from Golgi cells, providing temporally precise inhibitory input that narrows the window for the temporal summation of discrete mossy fiber inputs (6, 14, 18). This classical excitation–inhibition sequence forms the basis of a variety of contemporary cerebellar models (7, 9, 18, 19). However, the exact temporal relationship between sensory-evoked excitation and inhibition in granule cells has never been determined in vivo. Here, we combined in vivo whole-cell voltage-clamp recordings from granule cells and in vitro dynamic clamp experiments to investigate both the temporal dynamics of Golgi-cell–mediated inhibition and its importance for shaping sensory responses in the input layer of the cerebellum.