Abstract
Key points There is a rapid interneuronal response to focal activity in cortex, which restrains laterally propagating activity, including spreading epileptiform activity.The interneuronal response involves intense activation of both parvalbumin‐ and somatostatin‐expressing interneurons.Interneuronal bursting is time‐locked to glutamatergic barrages in the pre‐ictal period.Ca2+ imaging using conditional expression of GCaMP6f provides an accurate readout of the evolving firing patterns in both types of interneuron.The activation profiles of the two interneuronal classes are temporally offset, with the parvalbumin population being activated first, and typically, at higher rates. Previous work has described powerful restraints on laterally spreading activity in cortical networks, arising from a rapid feedforward interneuronal response to focal activity. This response is particularly prominent ahead of an ictal wavefront. Parvalbumin‐positive interneurons are considered to be critically involved in this feedforward inhibition, but it is not known what role, if any, is provided by somatostatin‐expressing interneurons, which target the distal dendrites of pyramidal cells. We used a combination of electrophysiology and cell class‐specific Ca2+ imaging in mouse brain slices bathed in 0 Mg2+ medium to characterize the activity profiles of pyramidal cells and parvalbumin‐ and somatostatin‐expressing interneurons during epileptiform activation. The GCaMP6f signal strongly correlates with the level of activity for both interneuronal classes. Both interneuronal classes participate in the feedfoward inhibition. This contrasts starkly with the pattern of pyramidal recruitment, which is greatly delayed. During these barrages, both sets of interneurons show intense bursting, at rates up to 300Hz, which is time‐locked to the glutamatergic barrages. The activity of parvalbumin‐expressing interneurons appears to peak early in the pre‐ictal period, and can display depolarizing block during the ictal event. In contrast, somatostatin‐expressing interneuronal activity peaks significantly later, and firing persists throughout the ictal events. Interictal events appear to be very similar to the pre‐ictal period, albeit with slightly lower firing rates. Thus, the inhibitory restraint arises from a coordinated pattern of activity in the two main classes of cortical interneurons.
Highlights
This delay appears to arise primarily from feedforward inhibition (Trevelyan et al 2007). This rapid interneuronal response could be argued to be the first recruitment to the ictal event, but we argue elsewhere (Trevelyan and Schevon, 2013; Trevelyan, 2016) that it is better to view this as the physiological response to the pathological ictal activity occurring in the adjacent territory, the final obstacle opposing the pathological spread
We reasoned that these cells might be the source of these inhibitory postsynaptic currents (IPSCs), a view consistent with prior reports of early recruitment of fast-spiking interneurons to ictal events (Kawaguchi, 2001; Timofeev et al 2002; Ziburkus et al 2006; Cammarota et al 2013; Librizzi et al 2017)
The zero Mg2+ in vitro model remains a mainstay of epilepsy research because of the insights it provides into the nature of the interneuronal response to surges of network activity
Summary
A new perspective on the spatial structure of seizures has been derived from detailed studies of propagating epileptic events recorded in brain slices (Wong and Prince, 1990; Trevelyan et al 2006; Trevelyan et al 2007; Losi et al 2010; Cammarota et al 2013; Sessolo et al 2015) and in vivo, in both animal models (Prince and Wilder, 1967; Dichter and Spencer, 1969; Schwartz and Bonhoeffer, 2001; Timofeev et al 2002; Timofeev and Steriade, 2004; Toyoda et al 2015) and during spontaneously occurring seizures in humans (Truccolo et al 2011; Schevon et al 2012; Weiss et al 2013; Weiss et al 2015). A key feature of this work has been to distinguish between two spatial patterns of activity: a core area, where all neurons are involved ( some might be pushed into depolarizing block; Ziburkus et al 2006; Sessolo et al 2015), and a second territory that is characterized by very large amplitude field potentials, but surprisingly low levels of activity, which we termed the ictal penumbra (Trevelyan and Schevon, 2013; Weiss et al 2013) This latter area appears to be the manifestation of a rapidly activated inhibition. We examine the pattern of interneuronal behaviour, immediately prior to the recruitment of the pyramidal cells
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