Anton Chizhov,
Dmytry Amakhin,
Elena Smirnova,
Aleksey ZaitsevNeurostars topic for Q&AEpileptic seizures and interictal discharges (IIDs) are determined by neuronal interactions and ionic dynamics and thus help to reveal valuable knowledge about the mechanisms of brain functioning in not only pathological but also normal state. As synchronized pathological discharges are much simpler to study than normal functioning, we were able to accomplish their description with a set of electrophysiological evidences constrained by a biophysical mathematical model. In the combined hippocampal-entorhynal cortex slices of rat in high potassium, low magnesium and 4-AP containing solution we evaluated separate AMPA, NMDA and GABA-A conductances for different types of IIDs, using an original experimental technique [1]. The conductances have shown that the first type of the discharges (IID1) is determined by activity of only GABA-A channels due to their pathologically depolarized reversal potential. The second type (IID2) is determined by an early GABA-A followed by AMPA and NMDA components. The third type is pure glutamatergic discharges observed in case of disinhibition. Our mathematical model of interacting neuronal populations reproduces the recorded synaptic currents and conductances for IIDs of the three types [2,3], confirming the major role of interneuron synchronization for IID1 and IID2, and revealing that the duration of IIDs is determined mainly by synaptic depression. IIDs occur spontaneously and propagate as waves with a speed of about a few tens of mm/s [4]. IDs are clusters of IID-like discharges and are determined by the ionic dynamics [5]. To reveal only major processes, main ions and variables, we have formulated a reduced mathematical model “Epileptor-2”, which is a minimal model that reproduces both IDs and IIDs [6] (Fig. 1). It shows that IIDs are spontaneous bursts that are governed by the membrane depolarization and synaptic resource, whereas IDs represent bursts of bursts. Important is the role of the Na/K-ATPhase. Potassium accumulation governs the onset of each ID. The sodium accumulates during the ID and activates the sodium-potassium pump, which terminates the ID by restoring the potassium gradient and thus repolarizing the neurons. A spatially-distributed version of the Epileptor-2 model reveals that it is not extracellular potassium diffusion but synaptic connectivity determines the speed of the ictal wavefront [7], which is consistent with our optogenetic experiments. The revealed factors are to be potential targets for antiepileptic medical treatment.
This work was supported by the Russian Science Foundation (project 16-15-10201).
References:
- Amakhin DV, Ergina JL, Chizhov AV, Zaitsev AV. Synaptic conductances during interictal discharges in pyramidal neurons of rat entorhinal cortex. Front. In Cell. Neurosc. 10:233, 2016.
- Chizhov A, Amakhin D, Zaitsev A. Computational model of interictal discharges triggered by interneurons. PLoS ONE 12(10):e0185752, 2017.
- Chizhov AV, Amakhin DV, Zaizev AV, Magazanik LG. AMPAR-mediated Interictal Discharges in Neurons of Entorhinal Cortex: Experiment and Model. Dokl Biol Sci. 479(1): 47-50, 2018. doi: 10.1134/S0012496618020011.
- Chizhov AV, Amakhin DV, Zaitsev AV. Spatial propagation of interictal discharges along the cortex. Biochem Biophys Res Commun. 508(4):1245-1251, 2019.
- Chizhov AV, Amakhin DV, Zaitsev AV. Mathematical model of Na-K-Cl homeostasis in ictal and interictal discharges. PLOS ONE. 2019;14(3):e0213904. doi:10.1371/journal.pone.0213904.
- Chizhov AV, Zefirov AV, Amakhin DV, Smirnova EY, Zaitsev AV. Minimal model of interictal and ictal discharges “Epileptor-2”. PLoS Comp. Biol. 14(5): e1006186, 2018. 31.
- Chizhov AV, Sanin AE (2020) A simple model of epileptic seizure propagation: Potassium diffusion versus axo-dendritic spread. PLoS ONE 15(4): e0230787.
Epileptor-2 code:
https://senselab.med.yale.edu/modeldb/ShowModel?model=263074#tabs-2Epileptor-2 online:
http://www.ioffe.ru/CompPhysLab/MyPrograms/Epileptor-2/Epileptor-2.html
