Ca²⁺-activated ion channels shape membrane excitability and Ca²⁺ dynamics in response to cytoplasmic Ca²⁺ elevation. Compared to the Ca²⁺-activated K⁺ channels, known as BK and SK channels, the physiological importance of Ca²⁺-activated Cl^- channels (CaCCs) in neurons has been largely overlooked. Here we report that CaCCs coexist with BK and SK channels in inferior olivary (IO) neurons that send climbing fibers to innervate cerebellar Purkinje cells for the control of motor learning and timing. Ca²⁺ influx through the dendritic high-threshold voltage-gated Ca²⁺ channels activates CaCCs, which contribute to membrane repolarization of IO neurons. Loss of TMEM16B expression resulted in the absence of CaCCs in IO neurons, leading to markedly diminished action potential firing of IO neurons in TMEM16B knockout mice. Moreover, these mutant mice exhibited severe cerebellar motor learning deficits. Our findings thus advance the understanding of the neurophysiology of CaCCs and the ionic basis of IO neuron excitability.

Ca²⁺-activated ion channels shape membrane excitability and Ca²⁺ dynamics in response to cytoplasmic Ca²⁺ elevation. Compared to the Ca²⁺-activated K⁺ channels, known as BK and SK channels, the physiological importance of Ca²⁺-activated Cl^- channels (CaCCs) in neurons has been largely overlooked. Here we report that CaCCs coexist with BK and SK channels in inferior olivary (IO) neurons that send climbing fibers to innervate cerebellar Purkinje cells for the control of motor learning and timing. Ca²⁺ influx through the dendritic high-threshold voltage-gated Ca²⁺ channels activates CaCCs, which contribute to membrane repolarization of IO neurons. Loss of TMEM16B expression resulted in the absence of CaCCs in IO neurons, leading to markedly diminished action potential firing of IO neurons in TMEM16B knockout mice. Moreover, these mutant mice exhibited severe cerebellar motor learning deficits. Our findings thus advance the understanding of the neurophysiology of CaCCs and the ionic basis of IO neuron excitability.