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 eye blink conditioning and adaptation of the vestibulo 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, we have developed several new protocols which have expanded the types of questions we may address: 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, we now undertake """"""""conventional"""""""" LTD experiments using a brain slice preparation. We propose to use these techniques to address the following questions. First, is cerebellar LTD, which we know 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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