Fast spiking interneuron control of seizure propagation in a cortical slice model of focal epilepsy

Abstract

Key points In focal epilepsy the propagation of seizure discharges arising at restricted brain sites is opposed by feedforward inhibition. Failure of this inhibition marks focal seizure propagation to distant neurons. The cellular source of inhibition and the mechanism of inhibition failure are, however, undefined. Here we reveal that a subclass of GABAergic interneurons, i.e. the parvalbumin‐expressing, fast‐spiking interneurons, are a main source of the inhibitory signal that locally restrains seizures. Furthermore, a firing impairment in these interneurons, probably due to a drastic membrane depolarization, is an important event that by reducing the overall strength of local inhibition allows seizures to propagate across the cortex. Our data suggest that modulation of fast‐spiking interneuron activity may represent a new therapeutic strategy to prevent generalization of focal epilepsies. Abstract In different animal models of focal epilepsy, seizure‐like ictal discharge propagation is transiently opposed by feedforward inhibition. The specific cellular source of this signal and the mechanism by which inhibition ultimately becomes ineffective are, however, undefined. We used a brain slice model to study how focal ictal discharges that were repetitively evoked from the same site, and at precise times, propagate across the cortex. We used Ca2+ imaging and simultaneous single/dual cell recordings from pyramidal neurons (PyNs) and different classes of interneurons in rodents, including G42 and GIN transgenic mice expressing the green fluorescence protein in parvalbumin (Pv)‐fast spiking (FS) and somatostatin (Som) interneurons, respectively. We found that these two classes of interneurons fired intensively shortly after ictal discharge generation at the focus. The inhibitory barrages that were recorded in PyNs occurred in coincidence with Pv‐FS, but not with Som interneuron burst discharges. Furthermore, the strength of inhibitory barrages increased or decreased in parallel with increased or decreased firing in Pv‐FS interneurons but not in Som interneurons. A firing impairment of Pv‐FS interneurons caused by a membrane depolarization was found to precede ictal discharge onset in neighbouring pyramidal neurons. This event may account for the collapse of local inhibition that allows spatially defined clusters of PyNs to be recruited into propagating ictal discharges. Our study demonstrates that Pv‐FS interneurons are a major source of the inhibitory barrages that oppose ictal discharge propagation and raises the possibility that targeting Pv‐FS interneurons represents a new therapeutic strategy to prevent the generalization of human focal seizures.

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

“…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. The failure of inhibition to control seizure activity in this model is caused by a depolarizing block of interneurons (Cammarota et al 2013), a phenomenon that was never shown in vivo.…”

“…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. The failure of inhibition to control seizure activity in this model is caused by a depolarizing block of interneurons (Cammarota et al 2013), a phenomenon that was never shown in vivo. A depolarizing block of the firing generated by inhibitory cells was also proposed as a seizure-initiation event in another model of acute seizures in the immature hippocampus in vitro (Derchansky et al 2006;Ziburkus et al 2006;Holler et al 2011).…”

Generation of physiological and pathological high frequency oscillations: the role of perisomatic inhibition in sharp-wave ripple and interictal spike generation

“…Aivar et al (201 4) [64] induced similar transitions from healthy to pathological forms of ripples by decreasing [Ca2+]e. They found similar shifts in excitability parameters and transmission parameters and concluded, similarly, that failure of inhibition results in strong PC firing that shapes the fRIPs. The importance of PVBCs in seizure propagation has been recently demonstrated [65]. It was also reported that some neurons can enter into depolarization blocks during seizures [66,67].…”

Dysfunction of hippocampal interneurons in epilepsy

“…In the medial entorhinal cortex of epileptic rats, the frequency and amplitude of sEPSCs in layer III interneurons are normal, while layer II stellate cells are hyperexcitable and receive a reduced frequency of spontaneous IPSCs and miniature IPSCs [8] . The inhibitory barrages in the pyramidal neuron (PyN) of the pair occur in coincidence with a burst in the PV-FS interneuron in both the 4-AP and the low Mg 2+ models in temporal cortex slices from G42 mice [27] .…”