Abstracts

Rationale:
Temporal lobe epilepsy (TLE) is characterized by recurrent seizures driven by synchronous neuronal activity. The dentate gyrus (DG) region of the hippocampal formation is highly reorganized in chronic TLE; in particular, pathological remodeling of the “dentate gate” is thought to open up pathological conduction pathways for synchronous discharges and seizures in the mesial temporal lobe. However, this pathophysiological framework lacks a mechanistic explanation of how macroscale synchronous dynamics emerge from alterations of the DG at the microcircuit level. In particular, the relative contribution of developmentally defined subpopulations of adult-born (abGCs) and mature (mGCs) granule cells to epileptiform network events remains unknown.
Method:
To address this question, we optically recorded calcium activity dynamics of identified populations of abGCs and mGCs using two photon microscopy, and recorded hippocampal local field potential during interictal epileptiform discharges (IEDs) in mice with chronic TLE. abGCs were birth dated for in vivo identification using tamoxifen inducible cre-expression under the nestin promoter, and subsequent expression of tdTomato. The unilateral intrahippocampal kainic acid model was used to induce chronic epilepsy, and mice were monitored with continuous video-EEG to assess the development of IEDs and seizures.
Results:
We find that disjoint subsets of IEDs differentially recruit abGC and mGC populations. We used these observations to develop a neural topic modeling framework, under which we find that the epileptic DG network organizes into disjoint, cell-type specific pathological ensembles, a subset of which are recruited by each IED. We found that statistics of this ensemble structure are highly conserved across animals, with abGCs disproportionately driving network activity in the epileptic DG during IEDs. 
Conclusion:
Our results provide the first in vivo characterization of activity dynamics of identified GC subpopulations in the epileptic DG, the first microcircuit-level correlates of IEDs in vivo, and reveal a specific contribution of abGCs to interictal epileptic events.
Funding:
:AES Junior Investigator Award, NIH R01NS094668