Cortico-hippocampal circuit dysfunction in a mouse model of Dravet syndrome
Abstract number :
5
Submission category :
1. Basic Mechanisms / 1B. Epileptogenesis of genetic epilepsies
Year :
2020
Submission ID :
2422354
Source :
www.aesnet.org
Presentation date :
12/5/2020 9:07:12 AM
Published date :
Nov 21, 2020, 02:24 AM
Authors :
Joanna Mattis, Hospital of the University of Pennsylvania; Jina Yom - University of Pennsylvania; Kevin Goff - University of Pennsylvania; Nathaniel Sotuyo - University of Pennsylvania; Keisuke Kaneko - Children's Hospital of Philadelphia; Huijie Feng - C
Rationale:
The temporal lobe is particularly vulnerable to seizures, and uncovering the circuit mechanisms of this vulnerability is crucial to the development of new 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. However, temporal lobe-onset seizures are also seen in genetic epilepsies, the etiology of which is entirely different. Here, we investigated cortico-hippocampal circuit pathology and ictogenesis in a well-characterized mouse model of a prominent genetic epilepsy (Scn1a+/- mice). We hypothesized that inhibitory dysfunction in Scn1a+/- mice would manifest as circuit-level dysfunction with impaired DG filtering of PP input, similar to that observed in models of acquired TLE.
Method:
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 adult (P48-91) and juvenile (P14-21) mice in acute slice. We quantified the response of activated GCs across a range of stimulus intensities using a mixed model analysis approach. We added optogenetic activation of parvalbumin (PV)-expressing cells (via ChrimsonR) to acutely rescue cortico-hippocampal hyperexcitability in Scn1a+/- mice. To assess the relevance of impaired cortico-hippocampal filtering for ictogenesis in vivo, we compared the effect of optogenetic stimulation of entorhinal cortex in Scn1a+/- versus wild-type control mice.
Results:
PP input resulted in a larger proportion of activated DG GCs, and a larger mean calcium signal amplitude, in adult Scn1a+/- mice versus wild-type controls (p < 0.001). There was no significant difference in a comparison of juvenile mice, suggesting that impaired filtering develops over or is unmasked with time. Concurrent optogenetic activation of PV cells in adult Scn1a+/- mice achieved a significant rescue, decreasing the GC response to approximately one third of that to PP stimulation alone (p < 0.001). When stimulating entorhinal cortex in vivo, no overt behavioral seizures were observed in wild-type mice, whereas Scn1a+/- mice had behavioral seizures at temperatures much lower than typical seizure threshold.
Basic Mechanisms