A guiding assumption in neurobiology has been that storage of information in the brain involves persistent, use-dependent alterations in synaptic strength. One useful model system for this endeavor has been cerebellar long-term depression (LTD), in which co-activation of climbing fiber and parallel fiber inputs to a Purkinje neuron (PN), induces a persistent, input-specific depression of the parallel fiber-PN synapse. This phenomenon has been suggested to be necessary for certain forms of motor learning including associative eyeblink conditioning and adaptation of the vestiblo-ocular reflex. Recently, the converse phenomenon, cerebellar long-term potentiation (LTP), has also been described in which the parallel fiber-PN synapse is strengthened by repetitive parallel fiber stimulation at intermediate frequencies, thus endowing this synapse with the capacity for use-dependent bidirectional modification, a computationally important property. In recent years, this laboratory has focused upon defining the requirements for LTD induction using a cell culture model system in which parallel fiber stimulation is replaced by glutamate pulses, and climbing fiber stimulation is replaced by direct depolarization of the PN. Most recently, several new protocols have been developed which have expanded the types of questions which may be addressed: sustained recordings from single PNs in culture to investigate the late phase of LTD, recordings from two ultra-reduced PN preparations that display LTD in the absence of dendritic spine compartments (acutely dissociated PNs and PN dendritic macropatches), and investigations of cerebellar LTP and LTD in granule cell-PN pairs in culture. In addition, """"""""conventional"""""""" LTD experiments using a brain slice preparation are now to be undertaken. These techniques will be used to address the following questions. First, is cerebellar LTD, which is known to be expressed postsynaptically, mediated by an alteration in AMPA receptor kinetics? Second, which intracellular signaling pathways are engaged by the late phase of cerebellar LTD? Third, what are the requirements for the induction of LTP at the granule cell-Purkinje cell synapse and where is its locus of expression? Finally, revisiting an ongoing controversy, what is the role of nitric oxide/cGMP signaling in cerebellar LTD induction? At the level of basic science, these investigations are central to an understanding of the cellular substrates of information storage in a brain area where the behavioral relevance of the inputs and outputs is unusually well defined. In addition, these investigations have potential clinical relevance not only for cerebellar motor disorders, but also for disorders of learning and memory generally.
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