An Integrated Approach to Synaptic Plasticity in the Hippocampus

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Synaptic plasticity is believed to be an important mechanism contributing to of learning, memory, and many aspects of development. There is significant evidence that in cortex synaptic plasticity contributes significantly to receptive field development. For example, in the hippocampus there is abundant cellular and molecular information about long term potentiation (LTP) and long term depression (LTD), the cellular manifestation of long lasting synaptic plasticity. LTP and LTD can be induced by different induction paradigms that depend on presynaptic rate, on pairing presynaptic spikes with postsynaptic depolarization, and on the precise time difference between pre and postsynaptic spikes. We have recently hypothesized that a single model, which depends on calcium influx through NMDA receptors can account for these different induction paradigms. Here we propose a more detailed study of the molecular dynamics, including improved but simple models of CaMKII and Calcinurin that underlie synaptic plasticity. Based on this detailed study as well as new experimental results and measured parameters, we will develop an updated version of the unified plasticity model (UPM) that can be quantitatively tested. We hypothesize that fluctuations in molecular dynamics can play a significant role in the resulting synaptic plasticity. We propose to analyze these fluctuations and calculate their effect on the different induction paradigms of synaptic plasticity. We also propose to test experimentally the validity of a key assumption of the UPM, that the back propagating action potential has a long tail, and to measure key physiological parameters in hippocampal cells. We will use measured physiological parameters in hippocampal cells in simulating the UPM in order to create a quantitative theory appropriate for the hippocampus. The UPM will be further developed to account for the maintenance phase of synaptic plasticity. We will also test the hypothesis that homeostatic metaplasticity is crucial in attaining stable, selective and robust fixed points.