The hippocampus plays an important role in memory formation. The most widely accepted theory of memory formation posits that information is stored through activity-dependent changes in synaptic strength, which in turn influence network, function and information storage in the hippocampus. Despite this well accepted notion, the detailed workings of hippocampal circuitry remain poorly understood. For instance, CA1 pyramidal neurons receive tens of thousands of synaptic inputs, but it is not known how synapses on different parts of the dendritic tree differentially influence action potential initiation. Here we propose experiments designed to improve our understanding of synaptic integration in the dendrites of CA1 pyramidal neurons. The proposed experiments will test an hypothesis concerning how synaptic inputs from the entorhinal cortex (perforant path) are integrated in the distal apical dendrites of CA1 neurons. Specifically, we propose that these synaptic inputs can only trigger axonal action potentials when they are strong enough to elicit dendritic spikes mediated by voltage-dependent sodium and calcium channels. We posit further that peforant path-induced dendritic spikes propagate to the soma only when more proximal synapses are activated or when plasticity leads to enhanced dendritic excitability. We propose that metabotropic glutamate receptor (mGluR)-dependent synaptic plasticity operates in concert with mGluR-dependent non-synaptic plasticity of dendritic excitability to enhance the ability of perforant path activation to lead to axonal action potential firing. These experiments will lead to a better understanding of how CA1 pyramidal neurons function within the context of a circuit employing plasticity to store memories. Such an improved understanding of the integrative properties of hippocampus is central to understanding the role of this brain structure in memory and how diseases such as epilepsy and Alzheimer's interfere with normal integrative function and memory.
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