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Review
. 2015 Nov 2;5(11):a022855.
doi: 10.1101/cshperspect.a022855.

Microcircuits in Epilepsy: Heterogeneity and Hub Cells in Network Synchronization

Anh Bui  1 , Hannah K Kim  1 , Mattia Maroso  1 , Ivan Soltesz  1
Affiliations
Review

Microcircuits in Epilepsy: Heterogeneity and Hub Cells in Network Synchronization

Anh Bui et al. Cold Spring Harb Perspect Med. .

Abstract

Epilepsy is a complex disorder involving neurological alterations that lead to the pathological development of spontaneous, recurrent seizures. For decades, seizures were thought to be largely repetitive, and had been examined at the macrocircuit level using electrophysiological recordings. However, research mapping the dynamics of large neuronal populations has revealed that seizures are not simply recurrent bursts of hypersynchrony. Instead, it is becoming clear that seizures involve a complex interplay of different neurons and circuits. Herein, we will review studies examining microcircuit changes that may underlie network hyperexcitability, discussing observations from network theory, computational modeling, and optogenetics. We will delve into the idea of hub cells as pathological centers for seizure activity, and will explore optogenetics as a novel avenue to target and treat pathological circuits. Finally, we will conclude with a discussion on future directions in the field.

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Figures

Figure 1.
Figure 1.
Neuronal cluster recruitment during epileptiform events. (A) Spatially localized clusters of neurons in the granule cell layer from tissue from an epileptic animal showing synchronous firing patterns are demarcated by polygons. (B,C) Spatial mapping and activation frequency of neuronal clusters from tissue from a control (B) and an epileptic animal (C). Lighter cluster shades indicate lower frequency of activation. (D, top) Raster plot of the activity of clusters diagrammed in A, represented by short vertical lines in corresponding colors; the height of the individual colored lines indicates the number of cells composing the cluster. Vertical gray lines extending the entire raster plot designate detected large-scale network events. (D, bottom) Fraction of active clusters over time. (From Feldt Muldoon et al. 2013; adapted, with permission, provided by the PNAS open access option.)
Figure 2.
Figure 2.
Granule cell hubs greatly increase dentate network excitability. (A) Schematic of a hub network. Granule cell hubs (gray diamonds) are four- to sevenfold more highly connected compared with average granule cells (black circles). (B and C) Raster plots of granule cell activity in a moderately injured dentate network (50% hilar cell loss, 50% of maximal mossy fiber sprouting) following perforant path stimulation to 1% of the cell population, where (B) new granule cell-to-granule cell connections are made randomly or (C) 5% of the granule cells serve as hubs. (From Morgan and Soltesz 2008; adapted, with permission, from the authors.)
Figure 3.
Figure 3.
Optogenetic suppression of neural activity in the hippocampus controls spontaneous seizure activity in the unilateral intrahippocampal kainate model of temporal lobe epilepsy. (A) To produce animals expressing halorhodopsin (HR) within excitatory neurons, CamKII-Cre animals were crossed with those carrying Cre-dependent HR. (B) Example of electrographic seizures detected (vertical green line) in Cam-HR mice, triggering delivery of no light or amber light (589 nm) to the hippocampus, as indicated by the amber line. (C–D) Data from Cam-HR mice showing the percentage of seizures that stop (C) within 5 sec of light stimulus, or (D) within 1 sec of light stimulus. (E) The normalized postdetection seizure duration. (F) To produce animals expressing channelrhodopsin (ChR2) within inhibitory neurons, animals expressing parvalbumin (PV)-Cre were crossed with those expressing Cre-dependent ChR2. (G) Example of electrographic seizures detected in PV-ChR2 mice, triggering the delivery of no light or blue light (473 nm), as indicated by the blue bar. (H–I) Data from PV-ChR2 mice showing (H) the percentage of seizures that stop within 5 sec of light stimulus, and (I) the normalized postdetection seizure duration. Error bars, s.e.m. (From Krook-Magnuson et al. 2013; adapted, with permission, from the authors.)
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