Corruption of the dentate gyrus by “dominant” granule cells: Implications for dentate gyrus function in health and disease

Abstract

The dentate gyrus (DG) and area CA3 of the hippocampus are highly organized lamellar structures which have been implicated in specific cognitive functions such as pattern separation and pattern completion. Here we describe how the anatomical organization and physiology of the DG and CA3 are consistent with structures that perform pattern separation and completion. We then raise a new idea related to the complex circuitry of the DG and CA3 where CA3 pyramidal cell ‘backprojections’ play a potentially important role in the sparse firing of granule cells (GCs), considered important in pattern separation. We also propose that GC axons, the mossy fibers, already known for their highly specialized structure, have a dynamic function that imparts variance – ‘mossy fiber variance’ – which is important to pattern separation and completion. Computational modeling is used to show that when a subset of GCs become ‘dominant,’ one consequence is loss of variance in the activity of mossy fiber axons and a reduction in pattern separation and completion in the model. Empirical data are then provided using an example of ‘dominant’ GCs – subsets of GCs that develop abnormally and have increased excitability. Notably, these abnormal GCs have been identified in animal models of disease where DG-dependent behaviors are impaired. Together these data provide insight into pattern separation and completion, and suggest that behavioral impairment could arise from dominance of a subset of GCs in the DG-CA3 network.

Pattern separation in the hippocampus through the eyes of computational modeling

“…While "dominant" GCs do not affect the overall activity of the DG, pattern separation is significantly impaired in a network model as these cells respond to all inputs, thus preventing the formation of separate DG representations (Scharfman & Myers, 2015).…”

“…The Scharfman lab introduced a number of simple, biologically relevant, models of the hippocampal DG‐CA3 microcircuit (Myers, Bermudez‐Hernandez, & Scharfman, ; Myers & Scharfman, ; Scharfman & Myers, ). In their first attempt, Myers and Scharfman used a simple network model of the DG (Myers & Scharfman, ), consisting of GCs, mossy cells (MCs), HIPP cells (HCs), and a general type of interneurons that played the role of basket (BCs) and chandelier cells, all modeled as point neurons.…”

“…A similar deficit in pattern separation has been proposed to emerge due to the formation of few “dominant” GCs (GCs that respond to all inputs) located within the GC layer of the DG (Larimer & Strowbridge, ; Thind, Ribak, & Buckmaster, ). While “dominant” GCs do not affect the overall activity of the DG, pattern separation is significantly impaired in a network model as these cells respond to all inputs, thus preventing the formation of separate DG representations (Scharfman & Myers, ).…”

“…Numerous computational studies have investigated how neurogenesis may contribute to learning and memory (Aimone et al, ; Appleby & Wiskott, ; Appleby et al, ; Becker, ; Chambers, Potenza, Hoffman, & Miranker, ; Deisseroth et al, ), including the abovementioned models of (Myers et al, ; Scharfman & Myers, ) that accounted for hEGCs and the “dominant” GC hypothesis, respectively. Specifically, given an elevated neurogenesis rate, some GCs were proposed to form an “ectopic” hilar population (Scharfman et al, ), while abGCs in the granule layer were considered to form a “dominant” GC population due to their high firing rates (Nakashiba et al, ).…”

Hormones and the regulation of adult neurogenesis in the hippocampus and beyond: Where are we now? Introduction to the special issue on hormonal regulation of adult neurogenesis: Implications for disease

“…Powerful genetic and molecular tools have led to the creation of model systems that will undoubtedly lead to more knowledge of the capability to produce new neurons. Given that there is still extensive research on the precise role of the hippocampus in memory (e.g., see Scharfman and Myers, 2016;Strange et al, 2014;Wixted and Squire, 2011), it should not be surprizing that we are still assessing the function of these new neurons (e.g., Cameron and Glover, 2015;Oomen et al, 2014).…”