Inhibitory Network Bistability Explains Increased Interneuronal Activity Prior to Seizure Onset

Abstract

Recent experimental literature has revealed that GABAergic interneurons exhibit increased activity prior to seizure onset, alongside additional evidence that such activity is synchronous and may arise abruptly. These findings have led some to hypothesize that this interneuronal activity may serve a causal role in driving the sudden change in brain activity that heralds seizure onset. However, the mechanisms predisposing an inhibitory network toward increased activity, specifically prior to ictogenesis, without a permanent change to inputs to the system remain unknown. We address this question by comparing simulated inhibitory networks containing control interneurons and networks containing hyperexcitable 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 driven by a brief perturbation. This transition into synchrony brings about a corresponding increase in overall firing rate. We further show that perturbations driving this transition could arise in vivo from background excitatory synaptic activity in the cortex. Thus, we propose that bistability explains the increase in interneuron activity observed experimentally prior to seizure via a transition from incoherent to coherent dynamics. Moreover, bistability explains why inhibitory networks containing hyperexcitable interneurons are more vulnerable to this change in dynamics, and how such networks can undergo a transition without a permanent change in the drive. We note that while our comparisons are between networks of control and ictogenic neurons, the conclusions drawn specifically relate to the unusual dynamics that arise prior to seizure, and not seizure onset itself. However, providing a mechanistic explanation for this phenomenon specifically in a pro-ictogenic setting generates experimentally testable hypotheses regarding the role of inhibitory neurons in pre-ictal neural dynamics, and motivates further computational research into mechanisms underlying a newly hypothesized multi-step pathway to seizure initiated by inhibition.

Novel microwire-based biosensor probe for simultaneous real-time measurement of glutamate and GABA dynamics in vitro and in vivo

“…In addition, baseline GABA decreased almost two minutes prior to the seizure, which was expected 46 , 72 . Furthermore, GABA and GLU increased just before the seizure, as others have shown 71 . GABA remained lower than baseline, as expected 47 , which likely contributed to the high E/I ratio.…”

“…The concurrent and sudden decrease in GABA and GLU with a rapid rebound to baseline of the interictal-like spikes warrants further study 59,60 . It is commonly reported that neurons fire in abnormal levels of synchrony during a seizure 71 . We also noticed that large fluctuations in concentration occurred at the same time, starting with interictal spiking and continued through the seizure even though the baseline levels of the two neurotransmitters changed independently from each other.…”

Neurostimulation stabilizes spiking neural networks by disrupting seizure-like oscillatory transitions

“…We provide mathematical evidence for the viability of this mechanism and show that extrinsic stimulation can be tuned to optimize this stabilizing effect. We note that a similar dynamic, a bistability in a purely inhibitory network, provides a mechanism underlying the increased interneuronal activity observed immediately prior to seizure onset in recent work 45 . Viewed together with this previous work, our results support a general hypothesis that stabilization of neural network dynamics away from sudden state transitions reduce their susceptibility to dynamics associated with the transition into seizure.…”

“…More importantly in the context of this study, and the mathematical exploration of this phenomenon, is that such behaviour is a signature of multi-stability: the existence of multiple stable solutions to a dynamical system. Indeed, such multi-stability represents a key feature of potential seizure-inducing mechanisms, often represented by a sudden transition into some form of oscillatory dynamics, both in vivo and in silico 45 , 55 , 62 , 77 , 78 . Both excitatory and inhibitory cells fire synchronously following the transition into oscillatory dynamics in our spiking networks (Fig.…”

Modeling reveals human-rodent differences in h-current kinetics influencing resonance in cortical layer 5 neurons

“…Finally, of interest is the relationship between h-channels, PIR, and epilepsy. Recent experimental (Chang et al, 2018) and computational (Rich et al, 2020) support has been presented for a novel hypothesis of seizure initiation, termed the “GABAergic initiation hypothesis”, which posits that excessive inhibitory signalling may trigger seizure via a cascade of events including PIR spiking in pyramidal cells. The experimental work of Chameh et al (2019) reveals that human cortical L5 pyramidal cells can exhibit PIR spiking under current-clamp conditions, likely driven by the dynamics of the h-channel.…”