Adult-born granule cells support pathological microcircuits in the chronically epileptic dentate gyrus

Abstract

Highlights• We relate electrographic signatures of epilepsy to microcircuit dynamics at single-cell resolution • The chronically epileptic dentate gyrus granule cell network is organized in lineagespecific pathological ensembles• A novel generative model framework for ensemble recruitment relates local field potential signatures to microcircuit activation during interictal epileptiform discharges • Adult-born granule cell-dominated ensembles are disproportionately represented among the inferred ensembles • The most active ensemble during an interictal epileptiform discharge can be decoded directly from the local field potential spectrum • This Latent Ensemble Recruitment model of cell recruitment by interictal events is the first application of Bayesian topic modeling to in vivo two-photon calcium imaging data Abstract 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 adultborn (abGCs) and mature (mGCs) granule cells to epileptiform network events remains unknown. To address this question, we optically recorded activity dynamics of identified populations of abGCs and mGCs during interictal epileptiform discharges (IEDs) in mice with chronic TLE. 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. 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.

Maximally selective single cell target for circuit control in epilepsy

“…Converging evidence has found similar statistical properties in pathological single-cell dynamics from larval zebrafish and mouse hippocampal dentate gyrus 17,30,31 . We therefore performed the same analysis in healthy control (N=3) and epileptic mice (intrahippocampal KA model; N=3) to address the question of whether our key findings in zebrafish acute seizure model held in the mammalian brain circuit and in a chronic model of TLE, the most prevalent form of epilepsy in adults.…”

“…For example, apparently self-repeating, macroscopically recurrent epileptiform LFP activity (inter-ictal spikes) indicating network synchrony have been shown to emerge from non-recurrent microscopic single-cell activity. In other words, each inter-ictal event is generated by a different combination of participating cells 17,30,31 . This ‘macro-micro’ disconnect 33 is a significant challenge for the field and indicates that a more nuanced understanding of pathways at the level of microcircuits is needed to treat the underlying disease 34 .…”

“…Three weeks post-KA injection, the video-EEG verified TLE mice were habituated to being head fixed under the two-photon microscope and concurrent Ca2+ imaging and LFP recording was performed. Detailed surgical procedures are reported in 31 .…”