Modeling implicates inhibitory network bistability as an underpinning of seizure initiation

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 April 11, 2019 1/36Recently, some studies of seizure initiation have shifted focus to over-activity of 25 inhibitory interneurons. This literature has yielded convincing evidence that 26 interneurons serve a causal role in seizure initiation [1,[8][9][10][11][12][13], laying the groundwork for 27 a novel hypothesis for seizure initiation (a "GABAergic initiation hypothesis") in which 28 synchronous activation of inhibitory interneurons precipitates the onset of a seizure, as 29 diagrammed in Fig 1 [12]. Given the contemporaneous nature of this hypothesis it is an 30ideal target for rigorous computational study; here, such research aims to unearth a 31 mechanism explaining the predisposition of inhibitory interneurons in a hyper-excitable 32April 11, 2019 2/36 environment to suddenly transition into synchrony, the necessary initial step in this 33 hypothesis. We thus focus on the earliest time in the transition to seizure and not 34 aspects of propagation and termination. 35The study of inhibitory network synchrony is decades old, dating back to the work of 36 Wang and Rinzel [14]. Various mechanisms have been proposed to explain the 37 generation of oscillations in purely inhibitory networks, the most prominent of which 38 may be the Interneuron Network Gamma (ING) mechanism [15-20]. Previous work has 39 shown that inhibitory networks built to examine population activity in an in vitro 40 hippocampal preparation manifest "sharp transitions" into coherent population activity 41 caused by a small, permanent increase to the external drive to the network [21]. 42 Additional studies have explored the effect of connection probabilities and cell 43 characteristics manifested by classifications of cell excitability on inhibitory network 44 synchrony [22, 23], and have noted that bist...

Reduced cholecystokinin-expressing interneuron input contributes to disinhibition of the hippocampal CA2 region in a mouse model of temporal lobe epilepsy

“…As seizure activity progresses the depolarizing effects of GABAergic signaling can further drive and synchronize population firing (Ellender, Raimondo, Irkle, Lamsa, & Akerman, 2014;Hamidi & Avoli, 2015;Huberfeld et al, 2007). This model is consistent with the reports of increased interneuron activity preceding seizures (Avoli & Curtis, 2011;Muldoon et al, 2015;Neumann & Soltesz, 2017;Rich et al, 2020), including PV+ interneurons specifically (Miri,…”