Loss of 4E-BP Converts Cerebellar Long-Term Depression to Long-Term Potentiation

Abstract

Genetic perturbances in translational regulation result in defects in cerebellar motor learning; however, little is known about the role of translational mechanisms in the regulation of cerebellar plasticity. We show that genetic removal of 4E-BP, a translational suppressor and target of mammalian target of rapamycin complex 1 (mTORC1), results in a striking change in cerebellar synaptic plasticity. We find that cerebellar long-term depression (LTD) at parallel fiber (PF)-Purkinje cell (PC) synapses is converted to long-term potentiation (LTP) in 4E-BP knockout mice. Biochemical and pharmacological experiments suggest that increased phosphatase activity largely accounts for the defects in LTD. Our results point to a model in which translational regulation through the action of 4E-BP plays a critical role in establishing the appropriate kinase/phosphatase balance required for normal synaptic plasticity in the cerebellum.