What the dentate gyrus and the millennial in your basement have in common.

Commentary What is the dentate gyrus (DG) good for? The answer may depend on whether or not you are interested in learning and memory, or epilepsy. While the actual circuitry is more complicated, the DG is the initial relay in the hippocampal circuit from the entorhinal cortex (EC). From there the DG projects to hippocampal sub-region Cornu Ammonis 3 (CA3), CA3 projects to hippocampal sub-region Cornu Ammonis 1 (CA1) and CA1 outputs back to the EC. Principal neurons in the EC project in the perforant path (PP) throughout the DG (convergence), while the number of principle neurons in the DG (dentate granule cells, DGCs) greatly exceeds the number of EC principle neurons (divergence) and their CA3 projections (1). While PP stimulation might be expected to result in exuberant DG (and CA3) activation, prior work has detailed that PP stimulation actually results in very spatially-selective and limited activation of the DG due to exuberant feed-forward and feedback inhibition activated by PP stimulation. To the neuroscientist interested in learning and memory, the DG is thus crucial for memory resolution or pattern separation (1, 2). To the epileptologist interested in epileptogenesis and seizure control, the DG is the crucial gate, limiting hippocampal activation in temporal lobe epilepsy (3). Given the impact of epilepsy on cognition, the role and function of the DG should be interesting to both. Surprisingly, how this circuit develops has not been fully explored. Further, comparative determination of single DGC behavior within the population of DGCs has not been studied; thus, it seems very appropriate and relevant to study. The authors addressed these gaps using two distinct functional imaging approaches applied to developing rodent (mice) hippocampus to address spatial activation of the hip-pocampal circuit as a whole and to investigate activation of individual DGCs within the circuit upon PP stimulation. While PP axons from EC and inhibitory interneurons are present in the DG from birth, DGCs begin to populate the DG around 2 to 3 weeks of age. The authors therefore investigated ventral/ temporal hippocampal slices obtained from approximately 2-, 3-, and 8-week-old rodents. The first imaging approach used a fluorescent dye, chemically introduced into nearly all cell membranes in the slice, which is sensitive to changes in membrane potential (voltage-sensitive dye imaging [VSDI]). This technique allowed the authors to investigate the network activation of the entire circuit from the DG, through the hilus of the DG, to CA3. Importantly, …