Quynh Anh Nguyen: Neural circuit mechanisms of pathological high frequency oscillations

Event Details:

Wednesday, June 1, 2022
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12:00pm to 12:00pm PDT
Event Sponsor
Wu Tsai Neurosciences Institute
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While most clinical treatments for epilepsy target seizure reduction, less is known about the effects of the abnormal activity that is continuously present in the epileptic brain presented as interictal spikes. Although studies have found the presence of interictal spikes can disrupt learning and memory processes, the underlying mechanism of how this disruption occurs remains to be determined. I 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. Mice receiving this focal knockout develop prominent interictal spikes as well as spontaneous seizures. I utilized a multi-scale approach to investigate the development and properties of interictal spikes in this model, and found that they 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, these pHFOs, while present only at the epileptic focus where the β3 subunit knockout occurred, can interfere with hippocampal network activity outside of the focus. Further investigation showed that these pHFOs emerge from a specific deficit in inhibitory synaptic transmission from PV interneurons to pyramidal cells located in the deep layer of the CA1 and are triggered by CA2 input. These findings demonstrate how alterations in particular microcircuits can have a profound impact on function at the cellular and network level, and ultimately lead to epilepsy. Ongoing work will utilize this newly developed model to explore novel avenues for targeted therapeutic intervention in temporal lobe epilepsy.

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