Feedforward Inhibition Contributes to the Control of Epileptiform Propagation Speed

Abstract

It is still poorly understood how epileptiform events can recruit cortical circuits. Moreover, the speed of propagation of epileptiform discharges in vivo and in vitro can vary over several orders of magnitude (0.1-100 mm/s), a range difficult to explain by a single mechanism. We previously showed how epileptiform spread in neocortical slices is opposed by a powerful feedforward inhibition ahead of the ictal wave. When this feedforward inhibition is intact, epileptiform spreads very slowly (ϳ100 m/s). We now investigate whether changes in this inhibitory restraint can also explain much faster propagation velocities. We made use of a very characteristic pattern of evolution of ictal activity in the zero magnesium (0 Mg 2ϩ ) model of epilepsy. With each successive ictal event, the number of preictal inhibitory barrages dropped, and in parallel with this change, the propagation velocity increased. There was a highly significant correlation ( p Ͻ 0.001) between the two measures over a 1000-fold range of velocities, indicating that feedforward inhibition was the prime determinant of the speed of epileptiform propagation. We propose that the speed of propagation is set by the extent of the recruitment steps, which in turn is set by how successfully the feedforward inhibitory restraint contains the excitatory drive. Thus, a single mechanism could account for the wide range of propagation velocities of epileptiform events observed in vitro and in vivo.

Initiation, Propagation, and Termination of Partial (Focal) Seizures

“…colleagues (2006, 2007) proposed that the increase of inhibitory network activity just ahead of a seizure may reflect the attempt of the network to impede seizure precipitation by imposing a feedforward inhibition on excitatory networks. When such inhibition fails, seizure activity characterized by hyperactivity of principal neurons ensues (Trevelyan et al 2006(Trevelyan et al , 2007. This interpretation was also suggested by Cammarota et al (2013), who analyzed the propagation of seizures induced by local application of N-methyl-D-aspartate (NMDA) in the entorhinal and temporal cortex in a brain slice preparation.…”

Glutamatergic pre-ictal discharges emerge at the transition to seizure in human epilepsy

“…Excitatory field events similar to PID have been detected just before seizures in animal models 6,8,15,43,44 . PID do not involve barrages of hyperpolarizing synaptic events which may act as an inhibitory restraint, to protect against the spread of seizure-like activities 45 . PID described here differ in that they are initiated near the site of seizure onset in epileptic subiculum rather before events spreading through healthy cortex in the presence of convulsants.…”

“…3b). The amplitude of stable PID (185±106 μV, 95% CI: , n=66 events from 8 slices) was significantly higher than that of simultaneous IID (49±24 μV, 95% CI: [42][43][44][45][46][47][48][49][50][51][52][53][54][55], n=66 events from 8 slices) (Wilcoxon test, Z(7)=3.99, P<0.01) (Fig. 3e) Fig.…”

Network Dynamics during Development of Pharmacologically Induced Epileptic Seizures in RatsIn Vivo

“…Studies based on intracellular recordings from brain slices or isolated hippocampi in vitro reported that seizure-like events are preceded by disruption of the inhibition-excitation balance, which can result from either reduction in inhibition or increased excitatory drive. In addition, it has been postulated that inhibitory interneurons participate in seizure initiation either by synchronizing large neuronal populations, via their wide spread and abundant connectivity, or by generating GABAergic-mediated depolarizing postsynaptic potentials (Wendling et al, 2002;Trevelyan et al, 2007;Derchansky et al, 2008).…”