Genetic Alteration of Tau Expression and Epileptogenesis After Intrahippocampal Kainate Treatment in Mice
Abstract number :
3.008
Submission category :
1. Basic Mechanisms / 1A. Epileptogenesis of acquired epilepsies
Year :
2022
Submission ID :
2204376
Source :
www.aesnet.org
Presentation date :
12/5/2022 12:00:00 PM
Published date :
Nov 22, 2022, 05:24 AM
Authors :
Madeleine Moseley, MS – Colorado State University; Ryan Cloyd, PhD – Physiology – University of Kentucky; Young-Jin Kang, PhD – Biomedical Sciences – Colorado State University; Sang-Hun Lee, PhD – Colorado State University; Rafael Roberts, BS – University of Kentucky; Bret Smith, PhD – Colorado State University
Rationale: New onset of seizure is a relatively common characteristic of neurodegenerative diseases involving tau pathology, including Alzheimer’s disease. Hyperphosphorylation of tau increases the excitability of neuronal networks and promotes susceptibility to induced seizures in several animal models of tauopathy. Similarly, removal of tau through genetic deletion or suppression with anti-sense oligonucleotides reduces seizure burden and improves survival in several animal models of induced seizures and epilepsy. We showed previously that dentate gyrus granule cells (DGCs) in tau-/- and htau mice exhibit signs of reduced cellular excitability around 1.5-2 months of age, relative to later in life and to non-transgenic control mice.
Methods: To determine whether this reduction in excitability associates with resistance to induced seizures or epileptogenesis, we treated 1.5-2 month old tau-/- and htau mice with an intrahippocampal injection of kainate (IHK). We assessed IHK-induced status epilepticus (SE) and the subsequent development of spontaneous seizures, and measured DGC excitability using whole-cell patch-clamp electrophysiology 6-8 weeks after IHK treatment.
Results: Changes in tau expression were associated with modifications in SE induction and epileptogenesis, but did not prevent either process. Preliminary data suggest that tau-/- mice exhibit fewer convulsive seizures after IHK compared to htau or non-transgenic mice, but electrographic monitoring revealed similar activity in all strains. Strikingly, mortality was significantly greater in htau mice 40 days after IHK, vs. other strains. The IHK-induced synaptic dysfunction detected in non-transgenic mice was abrogated in both transgenic strains.
Conclusions: These results suggest that strategies targeting tau may not prevent epileptogenesis outright but could show promise for disease modification, including effects on epilepsy related mortality.
Funding: NINDS 1R01NS092552, NCATS TL1TR001997, NIGMS 1T32GM118292
Basic Mechanisms