Climbing fibers selectively recruit disinhibitory interneurons to enhance dendritic calcium signaling in cerebellar Purkinje cells

Climbing fiber (CF) inputs to Purkinje cells (PCs) instruct plasticity and learning in the cerebellum1-3. Paradoxically, CFs also excite molecular layer interneurons (MLIs)4,5, a cell-type that inhibits PCs and can restrict plasticity and learning6,7. However, two types of MLIs with opposing influences have recently been identified: MLI1s inhibit PCs, reduce dendritic calcium signals, and suppress plasticity of granule cell to PC synapses2,6-9, whereas MLI2s inhibit MLI1s and disinhibit PCs8. To determine how CFs can activate MLIs without also suppressing the PC calcium signals necessary for plasticity and learning, we investigated the specificity of CF inputs onto MLIs. Serial EM reconstructions indicate that CFs contact both MLI subtypes without making conventional synapses, but more CFs contact each MLI2 via more sites with larger contact areas. Slice experiments indicate that CFs preferentially excite MLI2s via glutamate spillover4,5. In agreement with these anatomical and slice experiments, in vivo Neuropixels recordings show that spontaneous CF activity excites MLI2s, inhibits MLI1s, and disinhibits PCs. In contrast, learning-related sensory stimulation produced more complex responses, driving convergent CF and granule cell inputs that could either activate or suppress MLI1s. This balance was robustly shifted toward MLI1 suppression when CFs were synchronously active, in turn elevating the PC dendritic calcium signals necessary for LTD. These data provide mechanistic insight into why CF synchrony can be highly effective at inducing cerebellar learning2,3 by revealing a critical disinhibitory circuit that allows CFs to act through MLIs to enhance PC dendritic calcium signals necessary for plasticity.