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Abstract
Epileptic seizure is a paroxysmal and self-limited phenomenon characterized by abnormal hypersynchrony of a large population of neurons. However, our current understanding of seizure dynamics is still limited. Here we propose a novel in vivo model of seizure-like afterdischarges using optogenetics, and report on investigation of directional network dynamics during seizure along the septo-temporal (ST) axis of hippocampus. Repetitive pulse photostimulation was applied to the rodent hippocampus, in which channelrhodopsin-2 (ChR2) was expressed, under simultaneous recording of local field potentials (LFPs). Seizure-like afterdischarges were successfully induced after the stimulation in both W-TChR2V4 transgenic (ChR2V-TG) rats and in wild type rats transfected with adeno-associated virus (AAV) vectors carrying ChR2. Pulse frequency at 10 and 20 Hz, and a 0.05 duty ratio were optimal for afterdischarge induction. Immunohistochemical c-Fos staining after a single induced afterdischarge confirmed neuronal activation of the entire hippocampus. LFPs were recorded during seizure-like afterdischarges with a multi-contact array electrode inserted along the ST axis of hippocampus. Granger causality analysis of the LFPs showed a bidirectional but asymmetric increase in signal flow along the ST direction. State space presentation of the causality and coherence revealed three discrete states of the seizure-like afterdischarge phenomenon: 1) resting state; 2) afterdischarge initiation with moderate coherence and dominant septal-to-temporal causality; and 3) afterdischarge termination with increased coherence and dominant temporal-to-septal causality. A novel in vivo model of seizure-like afterdischarge was developed using optogenetics, which was advantageous in its reproducibility and artifact-free electrophysiological observations. Our results provide additional evidence for the potential role of hippocampal septo-temporal interactions in seizure dynamics in vivo. Bidirectional networks work hierarchically along the ST hippocampus in the genesis and termination of epileptic seizures.
Highlights
Epileptic seizure is a paroxysmal and self-limited phenomenon characterized by abnormal hypersynchrony of a large population of neurons [1,2,3]
A pattern of the induced activity can be substantially different from spontaneous seizures in humans [7,10,11,12,13,14]. This is a convenient model of epileptic seizures, the electrical stimulation generates large artifacts which interfere with neuronal activity recording in animal models, making it difficult to study the underlying physiological mechanism of the onset, propagation and cessation of seizure in vivo
Anti-seizure efficacy could be measured as a probability of afterdischarge induction in a short time
Summary
Epileptic seizure is a paroxysmal and self-limited phenomenon characterized by abnormal hypersynchrony of a large population of neurons [1,2,3]. Electrical kindling, the classic model of epileptogenesis, usually takes weeks to induce spontaneous seizures with less than 70% reproducibility [6,9]. A pattern of the induced activity can be substantially different from spontaneous seizures in humans [7,10,11,12,13,14]. This is a convenient model of epileptic seizures, the electrical stimulation generates large artifacts which interfere with neuronal activity recording in animal models, making it difficult to study the underlying physiological mechanism of the onset, propagation and cessation of seizure in vivo. Increasing the arsenal of seizure models is required to better pursue for the electrophysiological mechanisms underlying ictogenesis
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