Throughout life, the cerebellum plays a central role in the coordination and optimization of movements, using cellular plasticity to adapt a range of behaviors. Whether these plasticity processes establish a fixed setpoint during development, or continuously adjust behaviors throughout life, is currently unclear. Here, by spatiotemporally manipulating the activity of protein phosphatase 2B (PP2B), an enzyme critical for cerebellar plasticity in male and female mice, we examined the consequences of disrupted plasticity on the performance and adaptation of the vestibulo-ocular reflex (VOR). We find that, in contrast to Purkinje cell (PC)-specific deletion starting early postnatally, acute pharmacological as well as adult-onset genetic deletion of PP2B affects all forms of VOR adaptation but not the level of VOR itself. Next, we show that PC-specific genetic deletion of PP2B in juvenile mice leads to a progressive loss of the protein PP2B and a concurrent change in the VOR, in addition to the loss of adaptive abilities. Finally, re-expressing PP2B in adult mice that lack PP2B expression from early development rescues VOR adaptation but does not affect the performance of the reflex. Together, our results indicate that chronic or acute, genetic, or pharmacological block of PP2B disrupts the adaptation of the VOR. In contrast, only the absence of plasticity during cerebellar development affects the setpoint of VOR, an effect that cannot be corrected after maturation of the cerebellum. These findings suggest that PP2B-dependent cerebellar plasticity is required during a specific period to achieve the correct setpoint of the VOR.

在整个生命过程中，小脑在协调和优化运动方面发挥着核心作用，利用细胞可塑性来适应一系列行为。目前还不清楚这些可塑性过程是在发育过程中建立固定的设定点，还是在整个生命过程中不断调整行为。在这里，通过时空操纵蛋白磷酸酶 2B (PP2B)（一种对雄性和雌性小鼠小脑可塑性至关重要的酶）的活性，我们研究了可塑性破坏对前庭眼反射 (VOR) 的表现和适应的影响。我们发现，与出生后早期开始的浦肯野细胞（PC）特异性缺失相反，PP2B 的急性药理学以及成人发病的遗传缺失会影响所有形式的 VOR 适应，但不会影响 VOR 本身的水平。接下来，我们表明，幼年小鼠中 PC 特异性 PP2B 基因缺失除了导致适应能力丧失外，还会导致蛋白质 PP2B 逐渐丧失，同时 VOR 发生变化。最后，在早期发育时缺乏 PP2B 表达的成年小鼠中重新表达 PP2B 可挽救 VOR 适应，但不会影响反射的表现。总之，我们的结果表明 PP2B 的慢性或急性、遗传或药理学阻断会破坏 VOR 的适应。相比之下，只有小脑发育过程中可塑性的缺失才会影响 VOR 的设定点，这种影响在小脑成熟后无法纠正。这些发现表明，在特定时期需要依赖 PP2B 的小脑可塑性才能实现 VOR 的正确设定点。