Switching On Depression and Potentiation in the Cerebellum

Long-term depression (LTD) and long-term potentiation (LTP) in the cerebellum are important for motor learning. However, the signaling mechanisms controlling whether LTD or LTP is induced in response to synaptic stimulation remain obscure. Using a unified model of LTD and LTP at the cerebellar parallel fiber-Purkinje cell (PF-PC) synapse, we delineate the coordinated pre- and postsynaptic signaling that determines the direction of plasticity. We show that LTP is the default response to PF stimulation above a well-defined frequency threshold. However, if the calcium signal surpasses the threshold for CaMKII activation, then an ultrasensitive “on switch” activates an extracellular signal-regulated kinase (ERK)-based positive feedback loop that triggers LTD instead. This postsynaptic feedback loop is sustained by another, trans-synaptic, feedback loop that maintains nitric oxide production throughout LTD induction. When full depression is achieved, an automatic “off switch” inactivates the feedback loops, returning the network to its basal state and demarcating the end of the early phase of LTD. [Display omitted] •Unified bidirectional model of cerebellar parallel fiber-Purkinje cell LTD and LTP•An ultrasensitive on/off switch mechanism demarcates the early phase of LTD•A trans-synaptic feedback loop regulates nitric oxide production during LTD and LTP•LTP’s frequency dependence determined by stimulus-dependent nitric oxide secretion Gallimore et al. use a bidirectional model of parallel fiber-Purkinje cell long-term depression (LTD) and long-term potentiation (LTP) to delineate the trans-synaptic signaling pathways that control cerebellar plasticity. An ultrasensitive on/off switch demarcates the early phase of LTD, and a trans-synaptic feedback loop regulates nitric oxide production during LTD and LTP.