Cortical expression of AMPA receptors during postnatal development in a genetic model of absence epilepsy

Abstract

Childhood absence epilepsy has been associated with poor academic performance, behavioural difficulties, as well as increased risk of physical injury in some affected children. The frequent episodes of ‘absence’ arise from corticothalamocortical network dysfunction, with multifactorial mechanisms potentially involved in genetically different patients. Aberrations in glutamatergic neurotransmission has been implicated in some seizure models, and we have recently reported that reduced cortical AMPA receptor (AMPAR) expression (predominantly GluA4‐ containing AMPARs) in parvalbumin‐containing (PV+) inhibitory interneurons, could underlie seizure generation in the stargazer mutant mouse. In the present study, we investigate AMPA receptor subunit changes occurring during postnatal development in the stargazer mouse, to determine when these changes occur relative to seizure onset and thus could be contributory to seizure generation. Using quantitative western blotting, we analysed the expression of AMPAR GluA1‐4 subunits in the somatosensory cortex at three critical time points; two before seizure onset (postnatal days (PN) 7–9 and 13–15), and one at seizure onset (PN17–18) in stargazers. We report that compared to their non‐epileptic littermates, in the stargazer somatosensory cortex, there was a significant reduction in expression of AMPARs containing GluA1, 3 and 4 subunits prior to seizure onset, whereas reduction in expression of GluA2‐AMPARs appears to be a post‐seizure event. Thus, while loss of GluA4‐containing AMPARs (likely GluA1/4 and GluA3/4) may be linked to seizure induction, the loss of GluA2‐containing AMPARs is a secondary post‐seizure mechanism, which is most likely involved in seizure maintenance.

Targeting Ionotropic Glutamate Receptors in the Treatment of Epilepsy

“…Within current literature, this mostly applies to AMPA receptors and it is the consequence of the early overestimation of NBQX as a potential selective AMPA receptor antagonist. This led to a number of reports, which attributed to AMPA receptors a number of effects in the field of epilepsies; in contrast, these effects were due to a combined activation of AMPA and kainate receptors [ 47 , 48 , 52 , 80 - 82 ].…”

“…In contrast, after seizure activity, there is a reduced expression of GluA2- containing AMPA receptors. Therefore, one might argue that a loss of GluA4-containing AMPA receptors (likely GluA1/4 and GluA3/4 receptors) is linked to seizure induction, whereas a loss of GluA2-containing AMPA receptors contributes to seizure maintenance [ 82 ]. A specific loss in cortical-nRT excitation, leading to a reduced feed-forward inhibition of thalamic relay nuclei, characterizes the absence of epilepsy model of Gria4 knockout mice, which lack the GluA4 subunit [ 119 ].…”

Impact of Dysfunctional Feed-Forward Inhibition on Glutamate Decarboxylase Isoforms and γ-Aminobutyric Acid Transporters

“…Stargazer mice were obtained from Jackson Laboratories, USA. The breeding protocol for stargazer mice in this study was similar to our previously published work [8][9][10]. Heterozygous males were mated with either heterozygous females or homozygous females.…”

“…A lack of stargazin protein in the stargazer mouse model of absence epilepsy reduces the expression of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) at excitatory synapses onto feed-forward inhibitory (parvalbumin expressing; PV+) interneurons of the CTC network i.e., those in the somatosensory cortex (SScortex) [ 8 , 9 , 10 , 11 ] and reticular thalamic nuclei (RTN) of the thalamus) [ 12 , 13 ]. This deficit in stargazin, a transmembrane AMPAR transporting protein (TARP), impairs excitatory input to PV+ inhibitory interneurons, thus likely reducing FFI within the cortical and thalamic microcircuits of the CTC network.…”

The Impact of Glutamatergic Synapse Dysfunction in the Corticothalamocortical Network on Absence Seizure Generation

“…Research using the stargazer mouse model of absence epilepsy ( Barad et al, 2012 , 2017 ; Seo and Leitch, 2014 , 2015 , 2017 ; Adotevi and Leitch, 2016 , 2017 , 2019 ) has demonstrated that region-specific alterations in AMPA receptor expression in inhibitory microcircuits within the CTC network may be a key factor contributing to pathological hypersynchronous oscillatory activity in some forms of absence epilepsy. Specifically, a selective decrease in AMPA receptor expression at excitatory input synapses on RTN inhibitory interneurons from CT afferent projections (CT-RTN) but not at excitatory input synapses onto VP relay neurons (CT-VP) has been identified by Barad et al (2012) .…”