Repetitive electroconvulsive seizures induce activity of c-Jun N-terminal kinase and compartment-specific desensitization of c-Jun phosphorylation in the rat brain

Abstract Electroconvulsive seizures (ECS) are used for therapy of pharmacoresistent depression and are supposed to induce long-lasting neuronal alterations in morphology and gene expression. In this study, we have investigated the phosphorylation of the transcription factor protein c-Jun at its serine 73 residue by immunohistochemistry and the activity of the c-Jun N-terminal kinase 1 (JNK1) by immunocomplex assay following repetitive ECS in adult rats. In untreated controls, nuclear c-Jun immunoreactivity, but not N-terminal phosphorylation, was present in a variety of neuronal populations including the hippocampus, the temporobasal cortex and the amygdalar complex. Daily ECS for 1, 5 or 10 days (1×, 5× or 10× ECS) did not alter the expression of c-Jun but caused a substantial N-terminal phosphorylation of c-Jun (phospho-c-Jun). Nuclear phospho-c-Jun immunoreactivity was maximal within 15 min following ECS, and became absent after 30 min. The highest levels of phospho-c-Jun labeling were found after 1× ECS in the amygdalar complex, the dorsomedial hypothalamus and the piriform cortex. The inducibility of c-Jun N-terminal phosphorylation was preserved in the medial amygdala and piriform cortex, but significantly declined in the basal amygdala and medial hypothalamus with progressive ECS stimulation. One single ECS 3 or 5 days following 10× ECS yielded a pattern of phospho-c-Jun as seen following 10× ECS; thus, a lag of 5 days was not sufficient to provoke the initial level of N-terminal phosphorylation of c-Jun. In the dentate gyrus, c-Jun was not phosphorylated at any investigated time inspite of its high constitutive expression. In some contrast with this compartment-specific phosphorylation of c-Jun, immunocomplex assays revealed that the JNK1 activity was strongly enhanced in both amygdala and hippocampus. Our findings demonstrate that rapid JNK activation and phosphorylation of c-Jun as stand-by transcription factor characterize the beginning of neuroplastic changes, e.g., following ECS, a classic treatment of mental disorders. The N-terminal phosphorylation is compartment specific and can habituate following repetitive stimulation suggesting that the differential activation of the JNK/c-Jun axis is part of the neuronal strategy to integrate transynaptic excitation.