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

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 GABA(A) receptor (GABA(A)R) subunit expression in the stargazer primary somatosensory cortex (SoCx). Global tissue expression of GABA(A)R subunits alpha 1, alpha 3, alpha 4, alpha 5, beta 2, beta 3, gamma 2 and delta were assessed using Western blotting (WB), while biochemically isolated subcellular fractions were assessed for the alpha and delta subunits. We found significant reductions in tissue and synaptic expression of GABA(A)R alpha 1, 18% and 12.2%, respectively. However, immunogold-cytochemistry electron microscopy (ICC-EM), conducted to assess GABA(A)R alpha 1 specifically at synapses between PV+ interneurons and their targets, showed no significant difference. These data demonstrate a loss of phasic GABA(A)R alpha 1, indicating altered GABAergic inhibition which, coupled with dysfunctional FFI, could be one mechanism contributing to the generation or maintenance of absence seizures.

Automated summary

Absence seizures, characterized by hyperexcitations within the cortico-thalamocortical network, are believed to result from dysfunctional feed-forward inhibition. This study investigated the effects of dysfunctional inhibition on GABA(A) receptor subunit expression in the primary somatosensory cortex. The findings suggest altered GABAergic inhibition, potentially contributing to the generation or maintenance of absence seizures.