Abstracts

Rationale: While most clinical treatments for epilepsy target seizure reduction, little is known about the effects of the abnormal activity that is continually present in the epileptic brain presented as interictal spikes. While studies have found that the presence of interictal spikes can disrupt learning and memory processes, the underlying mechanism of how this disruption occurs and whether the effect is localized to the circuitry at the epileptic focus remains to be determined.

Methods: We have developed a novel mouse model of temporal lobe epilepsy using targeted knockout of the β3 subunit of the GABAA receptor, deficits of which have been implicated in epilepsy in humans, in CA1 pyramidal cells of the hippocampus. Animals receiving this focal knockout develop prominent interictal spikes as well as spontaneous seizures. We utilized 24-hour video EEG monitoring, 2-photon calcium imaging, silicon probe recording, and ex-vivo slice electrophysiology to investigate how loss of this molecular subunit leads to the development and effect of interictal spikes at the cellular, circuit, and behavioral scales.

Results: We found that interictal spikes are pathological high frequency oscillations (pHFOs) comprised of highly synchronous pyramidal cell firing which disrupt the ability of the cells to encode spatial information. In addition, while the presence of these pHFOs occur only in the hippocampal hemisphere where the focal knockout occurred, they can also interfere with the emergence of normal ripple oscillations, which are associated with learning and memory processes, in areas outside of the epileptic focus. We found that these pHFOs emerge from a particular deficit in the inhibitory synaptic transmission from PV interneurons to pyramidal cells located in the deep layer of the CA1 and are triggered by CA2 input.

Conclusions: Our findings pinpoint dysfunction in a particular hippocampal microcircuit in the development of interictal spikes and highlight how epileptic networks can cause significant impairments to neural functions important for learning and memory away from the seizure focus. These results demonstrate how treatments for epilepsy should also aim to reduce the emergence of interictal spikes and identify a potential circuit for more targeted therapeutic intervention.

Funding: Please list any funding that was received in support of this abstract.: NINDS T32NS007280, F32NS106764, K99NS121399 (Q.A.N.), R01NS094668 (I.S.), AES Postdoctoral Research Fellowship (B.D.), Canadian Institutes of Health Research Postdoctoral Research Fellowship (J.S.F), Stanford Interdisciplinary Graduate Fellowship (D.H.).