PP2B-dependent cerebellar plasticity sets the amplitude of an innate reflex during juvenile development

Abstract

Throughout life, the cerebellum plays a central role in the coordination and optimization of movements, using cellular plasticity to adapt a range of behaviors. If 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, 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 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 Purkinje cell-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 in 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 cerebellar plasticity influences behavior in two ways, through direct control of behavioral adaptation and via long-term effects initiated in the juvenile period. Significance StatementEarly damage to motor adaptation structures, such as the cerebellum, has been linked to neurodevelopmental disorders persisting into adulthood. Understanding these long-term effects requires disentangling the persistent, long-term effects of disrupted development from the acute, ongoing effects directly caused by the continuous presence of the disruption. Here, we demonstrate that disruptions during early development affect both basal level and adaptation, whereas late, adult-onset disruption of cerebellar plasticity only affects the ability to adapt, not the setpoint of an innate reflex. Our findings that specifically the absence of plasticity during cerebellar development affects the setpoint of VOR, which cannot be corrected by re-instating plasticity after maturation of the cerebellum, supports the concept of a sensitive developmental period for setting innate reflexes.