JNeurosci The Journal of Neuroscience

Tight Coupling of Astrocyte pH Dynamics to Epileptiform Activity Revealed by Genetically Encoded pH Sensors

Raimondo JV, Tomes H, Irkle A, Kay L, Kellaway L, Markram H, Millar RP, Akerman CJ

Contributed by Sloka Iyengar

Journal of Neuroscience 2016 Jun 29 Short title: pH changes in astrocytes in seizures, 36(26):7002-13. doi: 10.1523/JNEUROSCI.0664-16.2016

Studies have shown that neuronal pH during a seizure tends towards acidification. However, since astrocytes are important regulators of ionic homeostasis in the brain, what happens to astrocytic pH during a seizure might provide important clues about seizure initiation and propagation. The authors used genetically encoded pH reporters in organotypic hippocampal slice cultures, and found that astrocytes become rapidly alkaline during a seizure-like event. Also, pH changes in astrocytes are more closely linked to network activity than neuronal pH changes, and this rapid alkalinization is mediated by Na+/HCO3- cotransporters. This study helps broaden our understanding of pH alterations and seizure dynamics.

High-gamma (HG; 80-150 Hz) activity in macroscopic clinical records is considered a marker for critical brain regions involved in seizure initiation; it is correlated with pathological multiunit firing during neocortical seizures in the seizure core, an area identified by correlated multiunit spiking and low frequency seizure activity. However, the effects of the spatiotemporal dynamics of seizure on HG power generation are not well understood. Here we studied HG generation and propagation, using a three-step, multiscale signal analysis and modeling approach.

First, we analyzed concurrent neuronal and microscopic neetwork HG activity in neocortical slices from seven intractable epilepsy patients. We found HG activity in these networks, especially when neurons displayed paroxyysmal depolarization shifts and network activity was highly synchronized. Second, we examined HG activity acquired with microelectrode arrays recorded during numan seizures (nº=8). We confirmed the presence of syncronized HG power across microelectrode records and the macroscale, both specifically associated with the core region of the seizure. Third, we used volume conduction-based modeling to relate HG activity and network synchrony at different network scalses. We showed that local HG oscillations require high levels of synchrony to cross scales, and that this requirement is met at the microscopic scale, but not within macroscopic networks. Instead, we present evidence that HG power at the macroscale may result from harmonics of ongoing seizure activity. Ictal HG power marks the seizure core, but the generating mechanism can differ across spatial scales.

Summary for non-specialists