Junctophilin-mediated channel crosstalk essential for cerebellar synaptic plasticity

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Abstract
Functional crosstalk between cell‐surface and intracellular ion channels plays important roles in excitable cells and is structurally supported by junctophilins (JPs) in muscle cells. Here, we report a novel form of channel crosstalk in cerebellar Purkinje cells (PCs). The generation of slow afterhyperpolarization (sAHP) following complex spikes in PCs required ryanodine receptor (RyR)‐mediated Ca2+‐induced Ca2+ release and the subsequent opening of small‐conductance Ca2+‐activated K+ (SK) channels in somatodendritic regions. Despite the normal expression levels of these channels, sAHP was abolished in PCs from mutant mice lacking neural JP subtypes (JP‐DKO), and this defect was restored by exogenously expressing JPs or enhancing SK channel activation. The stimulation paradigm for inducing long‐term depression (LTD) at parallel fiber–PC synapses adversely established long‐term potentiation in the JP‐DKO cerebellum, primarily due to the sAHP deficiency. Furthermore, JP‐DKO mice exhibited impairments of motor coordination and learning, although normal cerebellar histology was retained. Therefore, JPs support the Ca2+‐mediated communication between voltage‐gated Ca2+ channels, RyRs and SK channels, which modulates the excitability of PCs and is fundamental to cerebellar LTD and motor functions.