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• W2936850520 abstract "Abstract A plethora of recent experimental literature implicates the abrupt, synchronous activation of GABAergic interneurons in driving the sudden change in brain activity that heralds seizure initiation. However, the mechanisms predisposing an inhibitory network toward sudden coherence specifically during ictogenesis remain unknown. We address this question by comparing simulated inhibitory networks containing control interneurons and networks containing hyper-excitable interneurons modeled to mimic treatment with 4-Aminopyridine (4-AP), an agent commonly used to model seizures in vivo and in vitro . Our in silico study demonstrates that model inhibitory networks with 4-AP interneurons are more prone than their control counterparts to exist in a bistable state in which asynchronously firing networks can abruptly transition into synchrony due to a brief perturbation. We further show that perturbations driving this transition could reasonably arise in vivo based on models of background excitatory synaptic activity in the cortex. Thus, these results propose a mechanism by which an inhibitory network can transition from incoherent to coherent dynamics in a fashion that may precipitate seizure as a downstream effect. Moreover, this mechanism specifically explains why inhibitory networks containing hyper-excitable interneurons are more vulnerable to this state change, and how such networks can undergo this transition without a permanent change in the drive to the system. This, in turn, potentially explains such networks’ increased vulnerability to seizure initiated by GABAergic activity. Author summary For decades, the study of epilepsy has focused on the hypothesis that over-excitation or dis-inhibition of pyramidal neurons underlies the transition from normal brain activity to seizure. However, a variety of recent experimental findings have implicated a sudden synchronous burst of activity amongst inhibitory interneurons in driving this transition. Given the counter-intuitive nature of these findings and the correspondingly novel hypothesis of seizure generation, the articulation of a feasible mechanism of action underlying this dynamic is of paramount importance for this theory’s viability. Here, we use computational techniques, particularly the concept of bistability in the context of dynamical systems, to propose a mechanism for the necessary first step in such a process: the sudden synchronization of a network of inhibitory interneurons. This is the first detailed proposal of a computational mechanism explaining any aspect of this hypothesis of which we are aware. By articulating a mechanism that not only underlies this transition, but does so in a fashion explaining why ictogenic networks might be more prone to this behavior, we provide critical support for this novel hypothesis of seizure generation and potential insight into the larger question of why individuals with epilepsy are particularly vulnerable to seizure." @default.
• W2936850520 created "2019-04-25" @default.
• W2936850520 creator A5020118492 @default.
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• W2936850520 date "2019-04-18" @default.
• W2936850520 modified "2023-09-23" @default.
• W2936850520 title "Modeling implicates inhibitory network bistability as an underpinning of seizure initiation" @default.
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• W2936850520 doi "https://doi.org/10.1101/613794" @default.
• W2936850520 hasPublicationYear "2019" @default.
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