Stress is the most commonly reported precipitating factor for seizures in patients with epilepsy. Despite compelling anecdotal evidence for stress-induced seizures, animal models of the phenomena are sparse and possible mechanisms are unclear. Here, we tested the hypothesis that increased levels of the stress-associated hormone corticosterone (CORT) would increase epileptiform activity and spontaneous seizure frequency in mice rendered epileptic following pilocarpine-induced status epilepticus. We monitored video-EEG activity in pilocarpine-treated mice 24/7 for a period of four or more weeks, during which animals were serially treated with CORT or vehicle. CORT increased the frequency and duration of epileptiform events within the first 24 hours of treatment, and this effect persisted for up to two weeks following termination of CORT injections. Interestingly, vehicle injection produced a transient spike in CORT levels – presumably due to the stress of injection – and a modest but significant increase in epileptiform activity. Neither CORT nor vehicle treatment significantly altered seizure frequency; although a small subset of animals did appear responsive. Taken together, our findings indicate that treatment of epileptic animals with exogenous CORT designed to mimic chronic stress can induce a persistent increase in interictal epileptiform activity.

Deletion of the mTOR pathway inhibitor PTEN from postnatally-generated hippocampal dentate granule cells causes epilepsy. Here, we conducted field potential, whole cell recording and single cell morphology studies to begin to elucidate the mechanisms by which granule cell-specific PTEN-loss produces disease. Cells from both male and female mice were recorded to identify sex-specific effects. PTEN knockout granule cells showed altered intrinsic excitability, evident as a tendency to fire in bursts. PTEN knockout granule cells also exhibited increased frequency of spontaneous excitatory synaptic currents (sEPSCs) and decreased frequency of inhibitory currents (sIPSCs), further indicative of a shift towards hyperexcitability. Morphological studies of PTEN knockout granule cells revealed larger dendritic trees, more dendritic branches and an impairment of dendrite self-avoidance. Finally, cells from both female control and female knockout mice received more sEPSCs and more sIPSCs than corresponding male cells. Despite the difference, the net effect produced statistically equivalent EPSC/IPSC ratios. Consistent with this latter observation, extracellularly evoked responses in hippocampal slices were similar between male and female knockouts. Both groups of knockouts were abnormal relative to controls. Together, these studies reveal a host of physiological and morphological changes among PTEN knockout cells likely to underlie epileptogenic activity.

During the development of epilepsy in adult animals, newly-generated granule cells integrate abnormally into the hippocampus. These new cells migrate to ectopic locations in the hilus, develop aberrant basal dendrites, contribute to mossy fiber sprouting and exhibit changes in apical dendrite structure and dendritic spine number. Mature granule cells do not appear to exhibit migration defects, basal dendrites and mossy fiber sprouting, but whether they exhibit apical dendrite abnormalities or spine changes is not known. To address these questions, we examined the apical dendritic structure of BrdU-birthdated, GFP-expressing granule cells born two months before pilocarpine-induced status epilepticus. In contrast to immature granule cells, exposing mature granule cells to status epilepticus did not significantly disrupt the branching structure of their apical dendrites. Mature granule cells did, however, exhibit significant reductions in spine density and spine number relative to age-matched cells from control animals. These data demonstrate that while mature granule cells are resistant to developing the gross structural abnormalities exhibited by younger granule cells, they show similar plastic rearrangement of their dendritic spines.