Excitatory Effects of Parvalbumin-Expressing Interneurons Maintain Hippocampal Epileptiform Activity via Synchronous Afterdischarges

Abstract

Epileptic seizures are characterized by periods of hypersynchronous, hyperexcitability within brain networks. Most seizures involve two stages: an initial tonic phase, followed by a longer clonic phase that is characterized by rhythmic bouts of synchronized network activity called afterdischarges (ADs). Here we investigate the cellular and network mechanisms underlying hippocampal ADs in an effort to understand how they maintain seizure activity. Using in vitro hippocampal slice models from rats and mice, we performed electrophysiological recordings from CA3 pyramidal neurons to monitor network activity and changes in GABAergic signaling during epileptiform activity. First, we show that the highest synchrony occurs during clonic ADs, consistent with the idea that specific circuit dynamics underlie this phase of the epileptiform activity. We then show that ADs require intact GABAergic synaptic transmission, which becomes excitatory as a result of a transient collapse in the chloride (Cl Ϫ ) reversal potential. The depolarizing effects of GABA are strongest at the soma of pyramidal neurons, which implicates somatic-targeting interneurons in AD activity. To test this, we used optogenetic techniques to selectively control the activity of somatic-targeting parvalbumin-expressing (PV ϩ ) interneurons. Channelrhodopsin-2-mediated activation of PV ϩ interneurons during the clonic phase generated excitatory GABAergic responses in pyramidal neurons, which were sufficient to elicit and entrain synchronous AD activity across the network. Finally, archaerhodopsin-mediated selective silencing of PV ϩ interneurons reduced the occurrence of ADs during the clonic phase. Therefore, we propose that activity-dependent Cl Ϫ accumulation subverts the actions of PV ϩ interneurons to perpetuate rather than terminate pathological network hyperexcitability during the clonic phase of seizures.

Activation of specific neuronal networks leads to different seizure onset types

“…39 Also, Cl -accumulation is greater and faster in smaller dendritic compartments in comparison to larger somas, thus allowing GABAergic activity to become depolarizing. 40 Finally, activation of both PV and SOM interneurons leads to the release of GABA, which has been shown to result in an increase in extracellular [K + ] regardless of target compartments. 41 …”

Selective Inhibition of KCC2 Leads to Hyperexcitability and Epileptiform Discharges in Hippocampal Slices andIn Vivo

“…However, KCC2 exhibits several transport-independent properties at excitatory synapses: (1) it binds scaffolding proteins within dendritic spines (Li et al, 2007); (2) it affects dendritic spine morphology (Fiumelli et al, 2013); (3) it influences the lateral membrane diffusion of AMPA receptors (Gauvain et al, 2011); and (4) it forms complexes with kainate receptors (Mahadevan et al, 2014). Because of these transporter-independent properties, it is unclear whether the vital and anticonvulsant roles of KCC2 are caused by its K ϩ /Cl Ϫ cotransport function.…”

GABAergic networks jump‐start focal seizures

“…3D). We should also mention that optogenetic studies have demonstrated that activation of GABAergic cells contributes to seizure maintenance 53 and can play a more conventional inhibitory role by contributing to the termination of ictal discharges.…”