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Reorganization of Dentate Gyrus Microcircuits During Epileptogenesis

  • Author(s): Jones, Ryan Thomas
  • Advisor(s): Mody, Istvan
  • Schweizer, Felix E
  • et al.
Abstract

Temporal lobe epilepsy (TLE) is a form of acquired epilepsy characterized by recurrent and unprovoked seizures. TLE often develops following a precipitating neurological insult, such as traumatic brain injury, stroke, infection, prolonged febrile seizures or status epilepticus. These insults can initiate a constellation of genetic, functional, network and systems level reorganization that transforms a normal non-epileptic brain into one capable of generating recurrent and unprovoked seizures. The period of time between neurological insults and the onset of epilepsy is known as the latent period and is believed to be the period of time during which underlying epileptogenic processes occur.

The dentate gyrus (DG) region of the hippocampus plays a key role in contextual learning and memory and strongly regulates the flow of neural activity from cortical regions into seizure-prone hippocampal regions through emergent properties of its neural microcircuit. In TLE, this filtering function is disrupted and can contribute to generation of seizures. Recent studies have described pathological high-frequency oscillations (pHFOs) in the DG and identified them as potential biomarkers of underlying proconvulsant network abnormalities. Moreover, pHFOs appear to be harbingers of TLE and are generated in the DG prior to the onset of an epileptic phenotype and therefore may reflect underlying network reorganization

during the epileptogenesis. Currently, little is known about the emergence of pHFOs after epilepsy-inducing neuronal insults or the pathological microcircuit that generates them. To address this we used a new mouse model of TLE to track the temporal and spectral evolution of pHFOs during epileptogenesis. Moreover, we investigated how disrupted integration of newly generated granule cells into the DG during epileptogenesis contributes to the disruption of DG microcircuit function.

We found that DG pHFOs are generated in bursts in vivo during epileptogenesis but that their burst properties do not evolve over time. In contrast, pHFO spectral dynamics appear to evolve during the latent period, suggesting that pHFO properties change according to the epileptogenic stage. In vitro electrophysiologcal and optogenetic experiments revealed that NGCs abnormally integrate into the DG microcircuit during epileptogenesis and that optogenetic activation of these neurons is sufficient to induce pHFOs in the DG.

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