Postnatal expression of thalamic GABAA receptor subunits in the stargazer mouse model of absence epilepsy

Seo, Steve; Leitch, Beulah

doi:10.1097/wnr.0000000000000909

Cited by 8 publications

(8 citation statements)

References 26 publications

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“…GABA A R are pentameric ligand-gated ionotropic chloride (Cl − ) channels that are ubiquitously expressed in the central nervous system. They mediate the majority of fast inhibitory neurotransmission, play a fundamental role in restraining and sculpting neuronal activity, and have been implicated in animal models of seizures 25 , 26 . There are 19 GABA A R subunits (α1–6, β1–3, γ1–3, δ, ε, θ, π, and ρ1–3) with the most prevalent synaptic isoform comprising two α1, two β2, and one γ2 subunit 27 , 28 .…”

Section: Introductionmentioning

confidence: 99%

Neocortex- and hippocampus-specific deletion of Gabrg2 causes temperature-dependent seizures in mice

Guo

et al. 2021

Cell Death Dis

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Mutations in the GABRG2 gene encoding the γ-aminobutyric acid (GABA) A receptor gamma 2 subunit are associated with genetic epilepsy with febrile seizures plus, febrile seizures plus, febrile seizures, and other symptoms of epilepsy. However, the mechanisms underlying Gabrg2-mediated febrile seizures are poorly understood. Here, we used the Cre/loxP system to generate conditional knockout (CKO) mice with deficient Gabrg2 in the hippocampus and neocortex. Heterozygous CKO mice (Gabrg2fl/wtCre+) exhibited temperature-dependent myoclonic jerks, generalised tonic-clonic seizures, increased anxiety-like symptoms, and a predisposition to induce seizures. Cortical electroencephalography showed the hyperexcitability in response to temperature elevation in Gabrg2fl/wtCre+ mice, but not in wild-type mice. Gabrg2fl/wtCre+ mice exhibited spontaneous seizures and susceptibility to temperature-induced seizures. Loss of neurons were observed in cortical layers V–VI and hippocampus of Gabrg2fl/wtCre+ mice. Furthermore, the latency of temperature- or pentylenetetrazol-induced seizures were significantly decreased in Gabrg2fl/wtCre+ mice compared with wild-type mice. In summary, Gabrg2fl/wtCre+ mice with Gabrg2 deletion in the neocortex and hippocampus reproduce many features of febrile seizures and therefore provide a novel model to further understand this syndrome at the cellular and molecular level.

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Section: Introductionmentioning

confidence: 99%

Neocortex- and hippocampus-specific deletion of Gabrg2 causes temperature-dependent seizures in mice

Guo

et al. 2021

Cell Death Dis

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“…Abnormal tonic inhibition in the stargazer VP thalamic nucleus has previously been reported [ 34 ]. Moreover, we also reported an increase in tonic GABA A R subunits α4 and δ levels in the VP thalamic nucleus, but only after the onset of seizures in the stargazers [ 28 , 30 ]. To assess whether any changes in tonic GABA A R subunits occur in the adult stargazer primary SoCx, we conducted further semiquantitative WB analyses to investigate levels of GABA A R α4, α5, and δ subunits.…”

Section: Resultsmentioning

confidence: 99%

“…In the stargazer ventroposterior (VP) thalamic nucleus, we previously reported a specific increase in both tonic and phasic GABA A R subunits [ 28 , 29 ]. However, unlike the AMPA receptor loss, which is pre-seizure, the increase in GABA A R subunits expression in the thalamus occurs after the onset of seizures [ 30 ], and thus is unlikely to be causative of seizures, although a role in seizure maintenance should not be ruled out. GABA A Rs generate either phasic or tonic post-inhibitory currents depending on synaptic or extra-synaptic GABAergic activation, respectively [ 31 ].…”

Section: Introductionmentioning

confidence: 99%

Altered GABAA Receptor Expression in the Primary Somatosensory Cortex of a Mouse Model of Genetic Absence Epilepsy

Hassan

Adotevi

Leitch

2022

IJMS

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Absence seizures are hyperexcitations within the cortico-thalamocortical (CTC) network, however the underlying causative mechanisms at the cellular and molecular level are still being elucidated and appear to be multifactorial. Dysfunctional feed-forward inhibition (FFI) is implicated as one cause of absence seizures. Previously, we reported altered excitation onto parvalbumin-positive (PV+) interneurons in the CTC network of the stargazer mouse model of absence epilepsy. In addition, downstream changes in GABAergic neurotransmission have also been identified in this model. Our current study assessed whether dysfunctional FFI affects GABAA receptor (GABAAR) subunit expression in the stargazer primary somatosensory cortex (SoCx). Global tissue expression of GABAAR subunits α1, α3, α4, α5, β2, β3, γ2 and δ were assessed using Western blotting (WB), while biochemically isolated subcellular fractions were assessed for the α and δ subunits. We found significant reductions in tissue and synaptic expression of GABAAR α1, 18% and 12.2%, respectively. However, immunogold-cytochemistry electron microscopy (ICC-EM), conducted to assess GABAAR α1 specifically at synapses between PV+ interneurons and their targets, showed no significant difference. These data demonstrate a loss of phasic GABAAR α1, indicating altered GABAergic inhibition which, coupled with dysfunctional FFI, could be one mechanism contributing to the generation or maintenance of absence seizures.

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“…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) .…”

Section: Introductionmentioning

confidence: 99%

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

Leitch

2022

Front. Mol. Neurosci.

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Childhood absence epilepsy (CAE) is the most common pediatric epilepsy affecting 10–18% of all children with epilepsy. It is genetic in origin and the result of dysfunction within the corticothalamocortical (CTC) circuitry. Network dysfunction may arise from multifactorial mechanisms in patients from different genetic backgrounds and thus account for the variability in patient response to currently available anti-epileptic drugs; 30% of children with absence seizures are pharmaco-resistant. This review considers the impact of deficits in AMPA receptor-mediated excitation of feed-forward inhibition (FFI) in the CTC, on absence seizure generation. AMPA receptors are glutamate activated ion channels and are responsible for most of the fast excitatory synaptic transmission throughout the CNS. In the stargazer mouse model of absence epilepsy, the genetic mutation is in stargazin, a transmembrane AMPA receptor trafficking protein (TARP). This leads to a defect in AMPA receptor insertion into synapses in parvalbumin-containing (PV+) inhibitory interneurons in the somatosensory cortex and thalamus. Mutation in the Gria4 gene, which encodes for the AMPA receptor subunit GluA4, the predominant AMPA receptor subunit in cortical and thalamic PV + interneurons, also leads to absence seizures. This review explores the impact of glutamatergic synapse dysfunction in the CTC network on absence seizure generation. It also discusses the cellular and molecular mechanisms involved in the pathogenesis of childhood absence epilepsy.

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Postnatal expression of thalamic GABAA receptor subunits in the stargazer mouse model of absence epilepsy

Cited by 8 publications

References 26 publications

Neocortex- and hippocampus-specific deletion of Gabrg2 causes temperature-dependent seizures in mice

Neocortex- and hippocampus-specific deletion of Gabrg2 causes temperature-dependent seizures in mice

Altered GABAA Receptor Expression in the Primary Somatosensory Cortex of a Mouse Model of Genetic Absence Epilepsy

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

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