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 the microtubule-associated protein tau. While genetic deletion or suppression of tau expression improves seizure outcomes in channelopathy models of genetic epilepsies we have found that there are differential effects of tau expression on seizures and epileptogenesis using the intrahippocampal kainate acid (IHK) model of acquired TLE. We aimed to investigate how tau expression alters synaptic neuronal excitability associated with TLE development to highlight potential circuit mechanism(s) by which lack of tau expression influences TLE development.
Methods:
To investigate how tau protein modifies the development of acquired TLE, we treated tau-/- and C57BL/6J mice with an IHK injection into the dorsal hippocampus. 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 and development of SRS using video-encephalography (v-EEG). We further measured cellular excitability and synaptic transmission in dentate granule cells (DGCs) in the ventral hippocampus (vHIPP) using whole-cell patch clamp electrophysiology to assess long-range synaptic reorganization.
Results:
We found that development of TLE is evoked at a lower rate in mice lacking tau expression after SE (p < 0.05) and v-EEG analysis of SRS revealed reduced spiking frequency during electrographic seizures (p < 0.01). We further measured the impact of tau expression on intrinsic excitability of ventral DGCs in mice that developed TLE. The development of TLE was associated with increased evoked action potential firing of DGCs ipsilateral and contralateral to IHK injection in wildtype controls (p < 0.05), while DGCs in tau-/- mice exhibited reduced action potential firing in DGCs contralateral to IHK injection (p < 0.05). We found no detectable differences in excitatory synaptic input to DGCs in mice of either genotype that developed TLE (p > 0.05). Interestingly, DGCs from tau-/- mice that developed TLE received increased inhibitory synaptic input compared to wildtype controls (p < 0.05). Further, we found that DGCs in naïve tau-/- mice received significantly less excitatory and inhibitory synaptic input compared to naïve wildtype mice (p < 0.05). Our results suggest that tau protein plays a role in synaptic transmission in the ventral dentate gyrus and that development of TLE in mice lacking tau expression reduces intrinsic excitability of DGCs and increases inhibitory synaptic input to DGCs.