Increased excitability of layer 5 neocortical pyramidal neurons and its contribution to seizure activity in Gabrg2 gene-deficient mice

<i>Gabrg2</i> ^<i>fl/wt</i> <i>Cre</i> ^<i>+</i> (CKO) mice are one of the models for studying "genetic epilepsy with febrile seizures plus (GEFS+)." A previous study revealed increased cortical excitability in CKO mice subjected to hyperthermia (CKO_-heat mice), but the mechanism remains unclear. We investigated electrophysiological and morphological changes in layer 5 (L5) pyramidal neurons (PNs), and related molecules expression in CKO_-heat mice. Hyperthermia increased the miniature excitatory postsynaptic current (mEPSC) increased, and decreased the miniature inhibitory postsynaptic current (mIPSC) in CKO mouse L5 PNs. The reduced complexity and dendritic spine density of in CKO mouse L5 PNs confirmed GEFS+-associated morphological changes. ITPR3 and GABRG2 (cytosolic protein) expression and the autophagosome number increased in the CKO mouse neocortex. These phenomena were attributed to PERK signaling pathway-mediated endoplasmic reticulum stress (ERS), which impaired vesicle transport. In summary, ERS reduces GABRG2 expression on the surface of L5 PNs in the CKO_-heat mouse neocortex. This mechanism may underlie GEFS+ onset.