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

Beulah Leitch1

  • 1Department of Anatomy, School of Biomedical Sciences, Brain Health Research Centre, University of Otago, Dunedin, New Zealand.

Frontiers in Molecular Neuroscience
|March 3, 2022
PubMed

Insights

Childhood absence epilepsy (CAE) involves corticothalamocortical (CTC) circuitry dysfunction. This review explores how AMPA receptor deficits in inhibitory interneurons contribute to CAE pathogenesis and pharmacoresistance.

Area of Science:

  • Neuroscience
  • Epileptology
  • Molecular Biology

Background:

  • Childhood absence epilepsy (CAE) is a common pediatric epilepsy originating from corticothalamocortical (CTC) circuitry dysfunction.
  • Genetic factors contribute to CAE, leading to variable responses to anti-epileptic drugs, with 30% of children being pharmacoresistant.
  • Dysfunction in AMPA receptor-mediated excitation of feed-forward inhibition (FFI) within the CTC network is implicated in absence seizure generation.

Purpose of the Study:

  • To review the impact of AMPA receptor-mediated excitation deficits in the CTC network on absence seizure generation.
  • To explore the cellular and molecular mechanisms underlying the pathogenesis of childhood absence epilepsy.
  • To discuss the role of glutamatergic synapse dysfunction in CAE.

Main Methods:

  • Literature review focusing on AMPA receptor function and dysfunction in epilepsy models.
  • Analysis of genetic mutations affecting AMPA receptor trafficking and subunits (stargazin, Gria4).
  • Examination of the role of parvalbumin-positive (PV+) inhibitory interneurons in the somatosensory cortex and thalamus.

Main Results:

  • Defects in AMPA receptor insertion into synapses of PV+ inhibitory interneurons, as seen in the stargazer mouse model (stargazin mutation), lead to absence seizures.
  • Mutations in the Gria4 gene, encoding the GluA4 AMPA receptor subunit prevalent in cortical and thalamic PV+ interneurons, also result in absence seizures.
  • Glutamatergic synapse dysfunction within the CTC network is a key factor in CAE.

Conclusions:

  • AMPA receptor trafficking and subunit composition are critical for normal function of inhibitory interneurons in the CTC network.
  • Dysfunction in AMPA receptor signaling contributes significantly to the generation of absence seizures in CAE.
  • Understanding these molecular mechanisms offers potential targets for novel therapeutic strategies for pharmacoresistant epilepsy.

Keywords:
AMPA receptorsDREADD technologyabsence epilepsycorticothalamocortical networkexcitatory synapsesfeed-forward inhibition

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