Abstracts

Tau Expression Modifies Development of Acquired Temporal Lobe Epilepsy Through Altered Inhibitory Synaptic Transmission in the Dentate Gyrus

Abstract number : 1.076
Submission category : 1. Basic Mechanisms / 1E. Models
Year : 2024
Submission ID : 997
Source : www.aesnet.org
Presentation date : 12/7/2024 12:00:00 AM
Published date :

Authors :
Presenting Author: Madeleine Moseley, MS – Colorado State University

Ryan Cloyd, MD – Indiana University
Liam Burns, BS – Colorado State University
Young-Jin Kang, PhD – Colorado St
Sanghun Lee, PhD – Colorado State University
Bret Smith, PhD – Colorado State University

Rationale: Temporal lobe epilepsy (TLE) is the most common focal epilepsy in adults and is often resistant to anti-epileptic drugs. Understanding the mechanisms that drive the development of TLE is crucial to developing new specific therapies. A potential target for treatment and/or prevention of epilepsy is microtubule-associated tau protein. For example, genetic deletion or suppression of tau expression improves seizure outcomes in channelopathy models of genetic epilepsies. Tau expression may alter synaptic function and neuronal excitability, but the mechanism(s) by which lack of tau expression influences seizure susceptibility or TLE development is unclear.


Methods: To determine the impact of tau expression on the development of acquired TLE, we treated tau-/- and C57BL/6J mice with an intrahippocampal injection of kainate (IHK). The IHK model induces status epilepticus (SE) in rodents and, after a delay, the development of TLE (i.e., epileptogenesis) with spontaneous recurrent seizures (SRS). We assessed the severity of SE and the development of SRS using video-encephalography (v-EEG). We further measured cellular excitability in dentate granule cells (DGCs) and GABAergic interneurons using whole-cell patch clamp electrophysiology.


Results: We found that SE and subsequent development of TLE is evoked at a lower rate in mice lacking tau expression (p < 0.05). While tau-/- mice exhibited no difference in SE severity once SE began, v-EEG analysis of SRS revealed reduced spiking frequency during electrographic seizures (p < 0.01). Analysis of power in naïve tau-/- mice revealed lower gamma power compared to wildtype controls, suggesting that tau expression influences inhibitory network activity (p < 0.001). We further measured the impact of tau expression on cellular excitability of DGCs. Our results demonstrate that DGCs in tau-/- mice receive less inhibitory input compared to wildtype controls (p < 0.05), while there were no detectable differences in excitatory input between groups. We further measured how cellular excitability of DGCs is altered after mice developed TLE. We found that inhibition of DGCs contralateral to IHK was increased in mice lacking tau expression after TLE development (p < 0.05). Using an AAV-mDlx construct, we recorded intrinsic properties of identified GABAergic interneurons in the dentate gyrus. Our results demonstrate increased intrinsic/synaptic excitability of interneurons in naïve tau
Basic Mechanisms