Use-dependent intrinsic plasticity in the cerebellum

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DESCRIPTION (provided by applicant): Modern theories of memory storage have largely focused on persistent, experience-dependent changes in synaptic function such as long-term synaptic potentiation and depression (LTP & LTD). These phenomena are appealing in models of memory, in part because they typically display some degree of synapse-specificity, allowing for a very large number of independently modifiable units and, consequently, a very large storage capacity. In addition to these synaptic changes, evidence has now emerged for persistent changes in intrinsic neuronal excitability, what we call "intrinsic plasticity", produced by certain forms of training in behaving animals and artificial patterns of activation in brain slices and neuronal cultures. These intrinsic changes may function as a portion of the engram itself, or as a related phenomenon such as a trigger for the consolidation or adaptive generalization of memories, particularly non-declarative memories. Several years ago, we published the first report of persistent synaptically driven changes in intrinsic excitability in the brain. This, in the deep cerebellar nuclei (DON), a region which is central to memory storage for certain tasks such as associative eyelid conditioning. We have since performed an extensive parametric description of the induction requirements and the expression of this phenomenon. Here, we propose to extend these initial observations by investigating the cellular and molecular basis of intrinsic plasticity in the DCN. First, we wish to characterize the receptors involved in intrinsic plasticity with particular emphasis on receptors for glutamate, serotonin and norepinephrine. Second, we will address the role of second messenger cascades including protein kinases, phosphatases, lipases and Ca stores. Third, we shall seek to identify the particular ion channel(s) involved in the expression of intrinsic plasticity through recording and occlusion experiments. Fourth, we shall use confocal imaging and uncaging to determine the spatial extent of intrinsic plasticity. This is basic research to address the molecular mechanisms that underlie memory storage, using an unusually well-defined model system. It is hoped that this work will be useful for creating therapies and diagnostics for diseases of memory. Because these cellular and molecular processes are not only involved in memory storage, this work has implications for other brain diseases as well, including epilepsy and addiction.