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Using Deep Two-Photon Microscopy to Test the Dentate Gate Hypothesis


Mesial temporal lobe epilepsy is the most common form of epilepsy in adults, but the underlying mechanisms are still not yet understood. Pathological changes in mTLE are prominent in the dentate gyrus (DG), a region important for regulating activity in the hippocampus and one of only two regions in the mammalian brain where adult neurogenesis occurs. Both human and animal studies of mTLE demonstrate defects in the migration and function of immature adult-born dentate granule cells. In this study, we gained further insight into mTLE using the pilocarpine murine model. Using a new generation of red calcium sensors and long wavelength two-photon excitation, we were able to image network activity within the intact hippocampus of awake behaving mice. This study took advantage of a surgical approach to implant a cranial imaging window on top of the hippocampus. Populations of labeled cells were chronically imaged in vivo. The DG in epileptic mice demonstrated synchronous firing, as seen by numerous flashes in the videos where multiple cells fired at the same time, which was not observed in the control mice. In vivo calcium imaging of the deeper brain tissue allows us to understand more about the dynamics of the layers, but this technique has its limitations. There were difficulties in obtaining a large enough sample size of mice as many cohorts of mice did not have the jRGECO protein expression in the DG. This study has set the groundwork for future experiments elucidating the role of immature adult-born DGCs in epileptogenesis.

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