Hello, everyone. My name is Simon Levinson, and I am a fourth-year medical student at the David Geffen School of Medicine at UCLA, and I'm going to be talking today about the role of the GABA receptor in pediatric epilepsy. Hello, everyone. My name is Simon. First off, though, I just want to state that since we submitted this abstract, this work has actually already been published, and all the figures you're going to see in this presentation are taken from our publication, which appeared in Frontiers of Cellular Neuroscience just a few weeks ago. I also really want to thank Dr. Carla Cepeda, who has been my research mentor for many years and has really helped me a ton through this process. The full paper itself is pretty wide-ranging, but I really want to focus here on a single key takeaway point, and that is the role of the GABA-B receptor and its implications. For some background, there are two major subtypes of GABA receptors, type A and type B, in the central nervous system. Type A is an ionotropic, fast receptor that is located postsynaptically, while type B is a metabotropic, slower, and located both pre- and postsynaptically and has multiple mechanisms of action. For a bit further background, it is thought that a reduction in function of the GABA-A receptor contributes to a breakdown in inhibitory neurotransmission. However, the role of the GABA-B receptor and its function is more poorly understood. Our aim, therefore, in this study was to use electrophysiological techniques to characterize the role of the GABA-B receptor in human tissue that was resected from pediatric patients with medically refractory focal epilepsy. I also want to define a couple of key terms for us. One of them is the drug 4-AP. That is a drug that's used to model epileptic activity in the lab, and it's a proconvulsant. Bicuculline blocks GABA-A receptors. Vaclifin blocks GABA-B receptors. And then paroxysmal discharges is a term that we use for recordings that we get from single cells in the lab that are a proxy for epileptic activity. Hello, everyone. My name is Simon. For the experimental setup, we use a cohort that consisted of a sample of tissue from a dataset that is made up of nearly 300 patients that's collected over 15 years, and all these patients underwent neurosurgery at UCLA for pediatric epilepsy. The pathologies include mostly cortical dysplasia and tuberous sclerosis complex, but there are also non-CD pathologies such as tumor, infarct, and Sturge-Weber syndrome. The pathologies that we saw are broken down here, and these are the ones that we used for this particular study. We'll see we used a total of 80 patients. The average age was about three years, and mostly we had pyramidal cells, but there were also interneurons and balloon cells as well, about a total of 240 cells. Hello, everyone. My name is Simon. Getting into some of the results, we can see here that when we use the drug 4-AP, which does not directly act on GABA receptors, but can be used to model epileptic activity to induce paroxysmal discharges, which are again our proxies for epileptic activity. We see here that an example of the paroxysmal discharges induced by 4-AP. Next, we applied the drug bicuculline, which is a GABA-A antagonist to demonstrate the role of the GABA-A receptor in producing paroxysmal discharges that we saw in the last slide. You can see both in the pyramidal and interneurons, there are far fewer spikes than we're seeing on the last slide, indicating that the GABA-A receptor was an essential component of the activity seen previously. Importantly, other measures we took showed that while 4-AP induced oscillations decreased, the overall network excitability actually increased, and interestingly, when we quantify and classify the type of activity observed at the cellular level into ICTL, which is activity that correlates with clinical seizure activity, and inter-ICTL, which does not directly correlate, none of the 31 cells treated in this condition produced ICTL-like activity, indicating even with GABA-A blockaded, there is still something preventing a catastrophic excitation of these cells. Hello everyone, my name is Simon. Now we ask the question, is GABA-B that force holding the cell back from full ICTL activity? We did this by applying a GABA-B antagonist, faclofen, to cells that had already had 4-AP and becuculline applied. We found that when we blockaded GABA-B, there is a significant enhancement of the paroxysmal discharges, and we did in fact see ICTL-like activity. Hello everyone, my name is Simon. Here are several more examples from single cells across multiple pathologies demonstrating a significant increase in activity when GABA-B is blockaded in addition to the blockade of GABA-A. Hello everyone, my name is Simon. Finally, when we quantitatively compare all the cells treated in both conditions, we see that only when GABA-B is blockaded do we see anything that can be classified as ICTL-like activity. Hello everyone, my name is Simon. So in conclusion, our data supports the hypothesis that the GABA-B receptor played a critical role in the transition from inter-ICTL to ICTL activity. We saw that when GABA-B receptors are functional, they can prevent a catastrophic excitation of other neurons. However, when they are disabled, ICTL activity is facilitated. Looking forward to the future, it is possible that allosteric modulators of the GABA-B receptor could prove to be beneficial, especially in patients whose epilepsy is not responsive to common antiepileptic drugs. Thank you.

GABA receptor

pediatric epilepsy

GABA-A receptor

GABA-B receptor

epileptic activity