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A low mortality, high morbidity Reduced Intensity Status Epilepticus (RISE) model of epilepsy and epileptogenesis in the rat
Animal models of acquired epilepsies aim to provide researchers with tools for use in understanding the processes underlying the acquisition, development and establishment of the disorder. Typically, following a systemic or local insult, vulnerable brain regions undergo a process leading to the development, over time, of spontaneous recurrent seizures. Many such models make use of a period of intense seizure activity or status epilepticus, and this may be associated with high mortality and/or global damage to large areas of the brain. These undesirable elements have driven improvements in the design of chronic epilepsy models, for example the lithium-pilocarpine epileptogenesis model. Here, we present an optimised model of chronic epilepsy that reduces mortality to 1% whilst retaining features of high epileptogenicity and development of spontaneous seizures. Using local field potential recordings from hippocampus in vitro as a probe, we show that the model does not result in significant loss of neuronal network function in area CA3 and, instead, subtle alterations in network dynamics appear during a process of epileptogenesis, which eventually leads to a chronic seizure state. The model’s features of very low mortality and high morbidity in the absence of global neuronal damage offer the chance to explore the processes underlying epileptogenesis in detail, in a population of animals not defined by their resistance to seizures, whilst acknowledging and being driven by the 3Rs (Replacement, Refinement and Reduction of animal use in scientific procedures) principles
Behavioral measurements of epilepsy following induction.
<p><b>A.</b> Distribution of weekly seizure frequency as observed during video monitoring (n = 10) <b>B.</b> Mean daily seizure frequency of animals during the recording period, data are expressed as mean ± SEM (n = 10). <b>C.</b> The percentage of animals meeting PSBB criteria at various weeks post-induction (n = 31). <b>D.</b> Touch x pickup and <b>E.</b> time bin pickup PSBB scores of animals having undergone <i>status</i> epilepticus induction (n = 37) and age-matched controls (criteria met/seizure observed, n = 13; criteria met/no seizure observed, n = 18; criteria not met/no seizure observed, n = 6; control, n = 12).</p
Spontaneous network activity in CA3 following establishment of SRS.
<p><b>A.</b> Raw data from CA3 recorded 90 days post-induction and in controls. Scale bar 200 ms x 50 μV. <b>B.</b> Power spectral density plots of the activity shown in A. <b>C.</b> Example Morlet-wavelet spectra and power spectral density plots of the same traces, white dotted lines on spectra indicate 20–60 Hz pseudo-frequency band. <b>C.</b> Pooled power and frequency plots for control and PSE 90d.</p
Spontaneous network activity in CA3 during the latent period.
<p><b>A.</b> Raw data from CA3 recorded during the latent period and in controls. Scale bar 200 ms x 50 μV. <b>B.</b> Power spectral density plots of the activity shown in A. <b>C.</b> Example Morlet-wavelet spectra and power spectral density plots of the same traces, white dotted lines on spectra indicate 20–60 Hz pseudo-frequency band. <b>C.</b> Pooled power and frequency plots for control and latent period.</p
Summary of <i>in vitro</i> network and behavioural observations at different stages of the RISE model.
<p>Summary of <i>in vitro</i> network and behavioural observations at different stages of the RISE model.</p
Appearance of ictal-like events in CA3 and mEC in vitro.
<p><b>A.</b> Example ictal-like event recorded in CA3 in slices from a PSE 101 day animal with confirmed SRS. Trace length 50 s. Blue box denotes expanded timescale (scale bar 950 ms x 550 μV). <b>B.</b> Example Morlet-wavelet spectrum of the area delineated by the blue box in A. <b>C.</b> Example recording made in CA3, CA1, layers V and II of mEC during an ictal-like event generated in mEC (scale bar 950 ms x 500 μV), a section is shown at an expanded temporal scale for clarity.</p