Modulating Cortico-Hippocampal Circuit Dysfunction in a Mouse Model of Dravet Syndrome
Abstract number :
3.023
Submission category :
1. Basic Mechanisms / 1B. Epileptogenesis of genetic epilepsies
Year :
2021
Submission ID :
1825828
Source :
www.aesnet.org
Presentation date :
12/6/2021 12:00:00 PM
Published date :
Nov 22, 2021, 06:50 AM
Authors :
Joanna Mattis, MD, PhD - Hospital of the University of Pennsylvania; Ala Somarowthu, PhD - Division of Neurology, Department of Pediatrics - Children's Hospital of Philadelphia; Kevin Goff, BS - Neuroscience Graduate Group, Perelman School of Medicine - University of Pennsylvania; Jina Yom, BS - College of Arts and Sciences - University of Pennsylvania; Nathaniel Sotuyo, BS - Neuroscience Graduate Group, Perelman School of Medicine - University of Pennsylvania; Laura McGarry, MD, PhD - Division of Neurology, Department of Pediatrics - Children’s Hospital of Philadelphia; Huijie Feng, PhD - Division of Neurology, Department of Pediatrics - Children’s Hospital of Philadelphia; Keisuke Kaneko, PhD - Division of Neurology, Department of Pediatrics - Children’s Hospital of Philadelphia; Ethan Goldberg, MD, PhD - Division of Neurology, Department of Pediatrics - Children’s Hospital of Philadelphia
Rationale: Improved understanding of the temporal lobe’s particular vulnerability to seizures may motivate development of new circuit-level epilepsy therapies. Studies using mouse models of acquired temporal lobe epilepsy (TLE) have identified a breakdown of dentate gyrus (DG) filtering of perforant path (PP) input, which may result in uncontrolled hyperexcitability and seizures. To test whether same breakdown is also seen in genetic epilepsies with temporal lobe-onset seizures, despite their different underlying etiologies, we investigated cortico-hippocampal circuit pathology and ictogenesis in the well-characterized mouse model of Dravet syndrome (Scn1a+/- mice). We hypothesized that Scn1a+/- mice would exhibit impaired DG filtering of PP input, and that this could be tuned by inhibiting or activating local GABAergic interneurons.
Methods: We used 2-photon calcium imaging with the genetically encoded calcium indicator GCaMP7s to determine the large-scale response of DG granule cells (GCs) to PP input in acute slice. We quantified the response of activated GCs across a range of stimulus intensities using a mixed model analysis approach. To assess the relevance of impaired cortico-hippocampal filtering for ictogenesis in vivo, we compared the effect of optogenetic stimulation (via ChR2) of entorhinal cortex in Scn1a+/- versus wild-type control mice. We then targeted local parvalbumin-expressing GABAergic inhibitory interneurons (PV-INs) with either chemogenetic inhibition (via hMD4Gi) or optogenetic activation (via ChrimsonR) to modulate cortico-hippocampal circuit excitability in Scn1a+/-mice.
Results: PP input resulted in a larger proportion of activated DG GCs, and a larger mean calcium signal amplitude, in young adult Scn1a+/- mice versus wild-type controls (p < 0.001). When stimulating entorhinal cortex in vivo, no overt behavioral seizures were observed in wild-type mice, whereas this stimulation was strongly ictogenic in Scn1a+/- mice. Chemogenetic inhibition of dentate PV-INs (in vivo) significantly lowered the temperature threshold for behavioral seizures in Scn1a+/- mice (p < 0.01) whereas optogenetic activation of PV-INs (in slice) decreased the Scn1a+/- GC response to approximately one third of that to PP stimulation alone (p < 0.001) thus achieving a significant circuit rescue.
Basic Mechanisms