Changes in excitatory and inhibitory receptor expression and network activity during induction and establishment of epilepsy in the rat Reduced Intensity Status Epilepticus (RISE) model

Gavin Woodhall,Jeremy M Henley,Damiana Cavallo,Sonam Gurung,Benjamin S Henley,Tamara Modebadze,Hope I Needs

doi:10.1016/j.neuropharm.2019.107728

Gavin Woodhall, Jeremy M Henley + Show 5 more

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https://doi.org/10.1016/j.neuropharm.2019.107728

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Journal: Neuropharmacology	Publication Date: Jul 26, 2019
Citations: 14	License type: cc-by

Affiliation: Aston University, University of Bristol

Abstract

The RISE model is an effective system to study the underlying molecular and cellular mechanisms involved in the initiation and maintenance of epilepsy in vivo. Here we profiled the expression of excitatory and inhibitory neurotransmitter receptor subunits and synaptic scaffolding proteins in the hippocampus and temporal lobe and compared these changes with alterations in network activity at specific timepoints during epileptogenesis. Significant changes occurred in all of the ionotropic glutamate receptor subunits tested during epilepsy induction and progression and the profile of these changes differed between the hippocampus and temporal lobe. Notably, AMPAR subunits were dramatically decreased during the latent phase of epilepsy induction, matched by a profound decrease in the network response to kainate application in the hippocampus. Moreover, decreases in the GABAAβ3 subunit are consistent with a loss of inhibitory input contributing to the perturbation of excitatory/inhibitory balance and seizure generation. These data highlight the synaptic reorganisation that mediates the relative hypoexcitability prior to the manifestation of seizures and subsequent hyperexcitability when spontaneous seizures develop. These patterns of changes give new insight into the mechanisms underpinning epilepsy and provide a platform for future investigations targeting particular receptor subunits to reduce or prevent seizures.

Highlights

Epilepsy is characterised by recurrent seizures caused by excessive neuronal activity in susceptible brain regions
There were highly significant changes in the levels of PSD95 in the hippocampus where PSD95 decreased by ~30% in Status Epilepticus (SE) and ~50% in latent period (LP) compared to age-matched controls (AMC) but, in stark contrast, there was a 3-fold increase in SRS (Fig. 1)
Dysregulation of the inhibitory/excitatory balance leading to excessive excitatory synaptic transmission, synaptic reorganisation and aberrant changes in neuronal circuits all contribute to the initiation and onset of epilepsy (Bozzi et al, 2012)

Summary

Introduction

Epilepsy is characterised by recurrent seizures caused by excessive neuronal activity in susceptible brain regions. Up to ~1% of the population worldwide suffer from epilepsy, equating to ~50 million people and, of these, ~40% have Temporal Lobe Epilepsy (TLE). Epilepsy can often be controlled with medication, ~30% of epilepsy cases are resistant to anti-epileptic drugs (AEDs) (WHO, 2018). Approximately a third of those initially responsive to AEDs will transition to drug-resistant epilepsy (DRE) during the course of the disease (Devinsky et al, 2018). There is an extensive, and sometimes contradictory, literature surrounding epileptogenesis and progression of TLE (for recent reviews see (Becker, 2018; Fukata and Fukata, 2017)).

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