Dynamical Changes in Neuronal Network Function Underlying Epileptogenesis in the Temporal Lobe

Abstract

Epilepsy is a common neurological disorder characterized by recurrent seizures. Even before the presentation of the first seizure, it is believed there is a chronic pathogenic process underlying the network, cellular and synaptic changes which result in the development of symptomatic epilepsy – termed epileptogenesis. Epileptogenesis involves several crucial, progressive steps which develop over a period of weeks, months or sometimes years: the initial precipitating assault/injury, the latent period, and spontaneous recurrent seizures (SRS). Understanding the development and progression of epileptogenesis within the temporal lobe offers a new avenue for controlling or even preventing the development of symptomatic epilepsy. Animal models of epilepsy allow researchers to investigate the pathogenic process’ of epilepsy and explore possible therapeutics, including anti-epileptic drugs. A low mortality, high morbidity model for epilepsy termed the reduced intensity status epilepticus (RISE) model was developed to study temporal lobe epilepsy. Investigation of the early stages of epileptogenesis involved ex vivo local field potential (LFP) and whole-cell patch clamp recordings of extracted brain slices from RISE animals during the latent period (weeks 2, 3, 4, 5, and 6 post-induction) and during the SRS stage of epileptogenesis (>3 months post-induction). Using several measures of brain excitability, it was found there is a marked reduction in brain excitability for RISE animals during the later stages of epileptogenesis (weeks 4 – 6 post-induction) compared to aged-matched control (AMC) in hippocampal subregions CA1 and CA3. However, there appears to be recovery to AMC or even above as animals enter SRS despite now displaying electrographic and behavioural seizures. Previous work studying the RISE model of epilepsy has uncovered a dramatic loss of the glutamatergic ionotropic AMPA receptors (AMPARs) and their associated accessory proteins in the hippocampus during the latent period which continues into SRS. Tianeptine is an atypical anti-depressant which is already known to modulate AMPAR function by increasing channel conductance and by increasing AMPAR trafficking and anchoring into the postsynaptic membrane. Control experiments confirmed this by revealing a marked increase in hippocampal gamma oscillatory power when conducting LFP experiments across all ages studied. Given the proposed mechanism of action of tianeptine, tianeptine (10µM) was then studied as a potential anti-epileptogenic drug to modify the progression of epileptogenesis within the RISE model. Ex vivo LFP and patch clamp recordings were taken and found tianeptine was able to recover the hippocampal oscillation during the early stages of epileptogenesis but had subregional differences as the epileptogenesis progressed. Under both spontaneous and kainic acid (KA) conditions, tianeptine had minimal effects on the gamma oscillations in both hippocampal subregions CA1 and CA3 during the latent period (6 weeks post-induction) compared to AMC. However, once RISE animals enter SRS, tianeptine was only capable of modulating gamma oscillations in CA1 (and not CA3) in KA conditions. Therefore, showing subregional differences in the progression of epileptogenesis. Finally, to explore seizure susceptibility, the 0 Mg2+ in vitro model of epilepsy was employed in the hippocampus. Using several measures, it was found RISE animals were more susceptible to generate seizures and seizure-like activity. Seizure susceptibility decreased as RISE animals entered later into the latent period (weeks 5 – 6 post-induction) and again increased as they entered SRS. This combines with the above findings of reduced brain excitability during the latent period which likely drives the progression of epileptogenesis into SRS. Overall, this thesis shows there are dynamical changes in neuronal network function which underlie epileptogenesis in the temporal lobe.