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A Million-Plus Neuron Model of the Hippocampal Dentate Gyrus: Critical Role for Topography in Determining Spatiotemporal Network Dynamics

Goal: This paper describes a million-plus granule cell compartmental model of the rat hippocampal dentate gyrus, including excitatory, perforant path input from the entorhinal cortex, and feedforward and feedback inhibitory input from dentate interneurons. Methods: The model includes experimentally determined morphological and biophysical properties of granule cells, together with glutamatergic AMPA-like EPSP and GABAergic GABAA-like IPSP synaptic excitatory and inhibitory inputs, respectively. Each granule cell was composed of approximately 200 compartments having passive and active conductances distributed throughout the somatic and dendritic regions. Modeling excitatory input from the entorhinal cortex was guided by axonal transport studies documenting the topographical organization of projections from subregions of the medial and lateral entorhinal cortex, plus other important details of the distribution of glutamatergic inputs to the dentate gyrus. Information contained within previously published maps of this major hippocampal afferent were systematically converted to scales that allowed the topographical distribution and relative synaptic densities of perforant path inputs to be quantitatively estimated for inclusion in the current model. Results: Results showed that when medial and lateral entorhinal cortical neurons maintained Poisson random firing, dentate granule cells expressed, throughout the million-cell network, a robust nonrandom pattern of spiking best described as a spatiotemporal “clustering.” To identify the network property or properties responsible for generating such firing “clusters,” we progressively eliminated from the model key mechanisms, such as feedforward and feedback inhibition, intrinsic membrane properties underlying rhythmic burst firing, and/or topographical organization of entorhinal afferents. Conclusion: Findings conclusively identified topographical organization of inputs as the key element responsible for generating a spatiotemporal distribution of clustered firing. These results uncover a functional organization of perforant path afferents to the dentate gyrus not previously recognized: topography-dependent clusters of granule cell activity as “functional units” or “channels” that organize the processing of entorhinal signals. This modeling study also reveals for the first time how a global signal processing feature of a neural network can evolve from one of its underlying structural characteristics.