Long-term depression (LTD) at the parallel fiber (PF)-to-cerebellar Purkinje cell (PC) synapse is implicated in the output of PCs, the sole output of the cerebellar cortex. In addition to synaptic plasticity, intrinsic excitability is also one of the components that determines PC output. Although long-term potentiation of intrinsic excitability (LTP-IE) has been suggested, it has yet to be investigated how PF-PC LTD modifies intrinsic excitability of PCs. Here, we show that pairing of the PF and climbing fiber (CF) for PF-PC LTD induction evokes LTD-IE in cerebellar PCs from male C57BL/6 mice. Interestingly, this intrinsic plasticity showed different kinetics from synaptic plasticity, but both forms of plasticity share Ca 2ϩ signaling and protein kinase C pathway as their underlying mechanism. Although smallconductance Ca 2ϩ -activated K ϩ channels play important roles in LTP-IE, no direct implication has been found. After PF-PC LTD induction, neither the temporal summation of dendritic EPSP nor the power of spike frequency adaptation is changed, indicating that cerebellar LTD executes the information processing in a quantitative way without quality changes of synaptic integration and generation of output signals. Our results suggest that LTD-IE may have a synergistic effect with synaptic depression on the total net output of neurons by amplifying the modification of PF synaptic transmission.

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Clinical studies have revealed that the cerebellum is activated by noxious stimuli or pathological pain, and its removal results in somatosensory dysfunction. However, the neural circuit, cellular and molecular mechanisms underlying pain transmission and modulation in the cerebellum remain unknown. Here, we show that Bergmann glia (BG) relay noradrenaline (NA) signals ascending from the locus coeruleus (LC) to Purkinje cells (PCs), contributing to pain behavior. Using two-photon microscopy and optogenetics in mice, we found that the LC releases NA in the cerebellar cortex during peripheral noxious electrical stimuli, which elevates intracellular calcium in most BG. This global calcium activation of BG, called 'flare', was also elicited during capsaicin-induced pain, and chemogenetic inactivation of BG or LC terminals inhibited not only BG flares but also pain behavior. Pharmacological blockade or genetic knockdown of BG alpha-1 adrenergic receptors (α1-ARs) also suppressed capsaicin-induced BG flares and pain behavior. Electrophysiological recordings indicated that capsaicin-induced pain accompanies the reduction of PC activity, which was mimicked by chemogenetic activation of BG and prevented when flares were blocked by prazosin, an α1-AR blocker. Taken together, our study identified a glia-mediated mechanism of cerebellar pain processing, providing new insights into the cerebellum as an active pain modulator.