System characterization of neuronal excitability in the hippocampus and its relevance to observed dynamics of spontaneous seizure-like transitions

Abstract

Most forms of epilepsy are marked by seizure episodes that arise spontaneously. The low-magnesium/high-potassium (low-Mg(2+)/high-K(+)) experimental model of epilepsy is an acute model that produces spontaneous, recurring seizure-like events (SLEs). To elucidate the nature of spontaneous seizure transitions and their relationship to neuronal excitability, whole-cell recordings from the intact hippocampus were undertaken in vitro, and the response of hippocampal CA3 neurons to Gaussian white noise injection was obtained before and after treatment with various concentrations of low-Mg(2+)/high-K(+) solution. A second-order Volterra kernel model was estimated for each of the input-output response pairs. The spectral energy of the responses was also computed, providing a quantitative measure of neuronal excitability. Changes in duration and amplitude of the first-order kernel correlated positively with the spectral energy increase following treatment with low-Mg(2+)/high-K(+) solution, suggesting that variations in neuronal excitability are coded by the system kernels, in part by differences to the profile of the first-order kernel. In particular, kernel duration was more sensitive than amplitude to changes in spectral energy, and correlated more strongly with kernel area. An oscillator network model of the hippocampal CA3 was constructed to investigate the relationship of kernel duration to network excitability, and the model was able to generate spontaneous, recurrent SLEs by increasing the duration of a mode function analogous to the first-order kernel. Results from the model indicated that disruption to the dynamic balance of feedback was responsible for seizure-like transitions and the observed intermittency of SLEs. A physiological candidate for feedback imbalance consistent with the network model is the destabilizing interaction of extracellular potassium and paroxysmal neuronal activation. Altogether, these results (1) validate a mathematical model for epileptiform activity in the hippocampus by quantifying and subsequently correlating its behavior with an experimental, in vitro model of epilepsy; (2) elucidate a possible mechanism for epileptogenesis; and (3) pave the way for control studies in epilepsy utilizing the herein proposed experimental and mathematical setup.

Low-to-High Cross-Frequency Coupling in the Electrical Rhythms as Biomarker for Hyperexcitable Neuroglial Networks of the Brain

“…was consistent with measurements made in low-Mg 2+ /high-K + models of epilepsy [20], [33]. This has been suggested to Fig.…”

“…Each unit consisted of a pyramidal cell, a fast-spiking interneuron, and an associated astrocyte. Four units were chosen, as that was previously found to be a minimal number of active neurons to be able to generate network effects [20]. As has been done in other studies, the rest of the network was represented by stochastic Poisson process [21] interacting with all of the pyramidal cells with a rate of 10 Hz [22].…”

Coupled Oscillators Model of Hyperexcitable Neuroglial Networks

“…/ High-K + experimental mouse model of epilepsy [119]. The network modeled the circuitry and rhythmicity of the CA3, with two CRGs representing pyramidal neuron populations and two representing interneuron populations (Fig.…”

“…The integrating mode, m(t), can be represented by an exponential impulse response function [119] [102]:…”

Seizure-like events in rodent and computer models: A ring device perspective

“…Similarly, extracellular low magnesium and elevated potassium in vitro epileptogenic preparations promote hyperexcitable conditions that favor the acute onset of spontaneous, recurrent SLEs [5]. If interconnected neuronal ensembles in the brain are treated as coupled network oscillators [5]- [7] or ring devices [8], then altering network properties in ring devices' model to mimic changes in excitability under epileptogenic conditions should allow for reproduction of epileptiform phenomena.…”