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.

An important feature of long-term synaptic plasticity is the prolonged maintenance of plastic changes in synaptic transmission. The trafficking of AMPA-type glutamate receptors (AMPARs) is involved in the expression of many forms of synaptic plasticity, yet the subsequent events accomplishing the maintenance of plastic changes in synaptic AMPAR numbers are not fully understood. Here, we find that maintenance of cerebellar long-term depression results from a reduction in the number of AMPARs residing within endocytic recycling pathways. We then develop a genetically encoded, photosensitive inhibitor of late endosome sorting and use this to discover that initial maintenance of long-term depression relies on timely regulated late endosome sorting, which exhibits a threshold as well as switch-like behavior. Thus, our results indicate that recycling AMPAR numbers are reduced by a switching machinery of transient late endosome sorting, and that this process enables the transition from basal synaptic transmission to long-term depression maintenance.

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