Epilepsy Fellow Hospital of the University of Pennsylvania Narberth, Pennsylvania
This abstract is a recipient of the Grass Foundation Young Investigator Award
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. 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 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. Conclusions: This work uses dynamic multicellular imaging and optogenetics in Scn1a+/- mice to link across scales and demonstrate a circuit-level abnormality and mechanism of ictogenesis in a well-validated preclinical experimental model of epilepsy. This supports the compelling idea that abnormal cortico-hippocampal circuitry may be a common finding between genetic and acquired mechanisms of temporal lobe-onset seizures. This circuit hyperexcitability can be acutely rescued by activation of PV cells, suggesting that correction of deficits in this cell population reconstitutes normal cortico-hippocampal function and could be used as a strategy to treat or prevent epilepsy. Funding: Please list any funding that was received in support of this abstract.: This work was supported by NIH NINDS Research Education Grant (R25) to J.M. and the NIH NINDS K08 NS097633, NIH NINDS R01 NS110869, and Burroughs Wellcome Fund Career Award for Medical Scientists to E.M.G.
