Regulation of hippocampal Fas receptor and death-inducing signaling complex after kainic acid treatment in mice

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Abstract

Kainic acid (KA)-induced brain neuronal cell death (especially in the hippocampus) was shown to be mainly mediated by the intrinsic (mitochondrial) apoptotic pathway. This study investigated the regulation of the extrinsic apoptotic pathway mediated by Fas ligand/Fas receptor and components of the indispensable death-inducing signaling complex (DISC) in the hippocampus (marked changes) and cerebral cortex (modest changes) of KA-treated mice. KA (45 mg/kg) induced a severe behavioral syndrome with recurrent motor seizures (scores; maximal at 60–90 min; minimal at 72 h) with activation of hippocampal pro-apoptotic JNK (+ 2.5 fold) and increased GFAP (+ 57%) and nuclear PARP-1 fragmentation (+ 114%) 72 h post-treatment (delayed neurotoxicity). In the extrinsic apoptotic pathway (hippocampus), KA (72 h) reduced Fas ligand (− 92%) and Fas receptor aggregates (− 24%). KA (72 h) also altered the contents of major DISC components: decreased FADD adaptor (− 44%), reduced activation of initiator caspase-8 (− 47%) and increased survival FLIP-S (+ 220%). Notably, KA (72 h) upregulated the content of anti-apoptotic p-Ser191 FADD (+ 41%) and consequently the expression of p-FADD/FADD ratio (+ 1.9-fold), a neuroplastic index. Moreover, the p-FADD dependent transcription factor NF-κB was also increased (+ 61%) in the hippocampus after KA (72 h). The convergent adaptation of the extrinsic apoptotic machinery 72 h after KA in mice (with otherwise normal gross behavior) is a novel finding which suggests the induction of survival mechanisms to partly counteract the delayed neuronal death in the hippocampus.

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