Dissecting microcircuit alterations in the epileptic dentate gyrus with functional imaging

点击翻译按钮获取中文摘要

Temporal lobe epilepsy (TLE) is a common neurological disorder affecting up to 1 in 100 people and characterized by recurrent focal seizures. These seizures are driven by synchronous neuronal activity originating in the mesial temporal lobe, most commonly the hippocampal formation. The dentate gyrus region of the hippocampal formation is highly reorganized in chronic TLE; disease-associated remodeling of the “dentate gate” is thought to open up pathological conduction pathways for synchronous discharges and seizures to propagate through the mesial temporal lobe. However, this pathophysiological understanding lacks a mechanistic explanation of how macroscale synchronous dynamics emerge from alterations of the dentate gyrus at the microcircuit level. In particular, how the collective activity of the four principal populations of the dentate gyrus, i.e., adult-born and mature granule cells, mossy cells, and interneurons, gives rise to epileptiform network-level events remains unknown. This proposal aims to characterize the activity of these populations during interictal events and seizures, and test a theoretical model of the emergence of macrolevel network events from the activity of microlevel ensembles. To address this question, I will use simultaneous in vivo two-photon calcium imaging and local field potential recordings in behaving mice in the intrahippocampal kainic acid model of epilepsy to optically record activity dynamics of genetically identified populations in the dentate gyrus in mice with chronic TLE, and correlate them with macrolevel features of the local field potential. In Aim 1, I will characterize these four populations in the interictal period, during pathological interictal events, and during seizures. Recent work in vitro work has shown that distinct ensembles of dentate gyrus neurons fire during interictal events. In Aim 2, I propose a mechanistic generative model for the recruitment of microcircuits by macroscale epileptiform events. This model predicts that network activity during interictal events provides a series of snapshots of the pathological structure that allows the chronically epileptic network to support seizures. The experiments and modeling described here will provide the first in vivo characterization of activity dynamics of the principal neuronal populations of the epileptic dentate gyrus, and have the potential to unify microscopic and macroscopic narratives of the disease.