Dentate mossy cells are a relatively rare population of neurons that are extremely vulnerable to excitotoxic damage from excess excitatory input. While the cellular mechanisms responsible for this vulnerability are not known, one potential explanation lies in the unusual ability of mossy cells to modulate the strength of their own synaptic inputs. I observed that following short periods of intracellularly-injected depolarizing current pulses, there was a dramatic and prolonged enhancement of spontaneous excitatory postsynaptic potentials (EPSPs) recorded in that same cell. I hypothesized that this phenomenon, depolarization-related potentiation, may contribute to the vulnerability of the mossy cells by generating a positive feedback pathway: relatively brief periods of depolarization, such as experienced when several spontaneous EPSPs overlap, may engage this mechanism--potentiating subsequent EPSPs and creating the potential for a runaway depolarization and cell death. This type of progressive depolarization, initiated by large amplitude EPSPs, has been observed in an in vitro model of temporal lobe epilepsy in which mossy cells are selectively vulnerable. The experiments in rat hippocampal slices outlined in this proposal are designed to uncover the mechanisms that underlie this form of plasticity. We focus first on the mechanisms of plasticity at the granule cell/mossy cell synapse since my preliminary data suggests that much of DRP could be explained by modulation of this synapse. By examining properties of miniature EPSCs before and after induction of DRP, we hope to ascertain whether the pre- or postsynaptic site is modulated by DRP, and thus whether DRP represents a form of trans-synaptic plasticity. Preliminary experiments suggest that DRP shares many similarities with short-term potentiation (STP) studied in the hippocampus; we anticipate that the experiments proposed here will lead to new understanding of general principles of synaptic potentiation. The potential role calcium accumulation in the mossy cells in the induction of DRP will be tested using calcium chelators and the calcium-sensitive fluorescent dye, fura-2. We then will examine the contribution to the potentiation from spiking in other dentate and hippocampal neurons which are synaptically coupled to mossy cells using dual recordings and slices in which subfields of the hippocampus and/or dentate gyrus have been removed. I anticipate that these studies will determine if a form of """"""""self-potentiation"""""""" is responsible for the excitotoxic damage to hilar neurons in vitro and may lead to new insights into the etiology of hippocampal-onset temporal lobe epilepsy.
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