Long-term exposure to anti-GluA3 antibodies triggers functional and structural changes in hippocampal neurons

Autoantibodies targeting the GluA3 subunit of AMPA receptors (AMPARs) are implicated in various neurological disorders, including Rasmussen’s encephalitis, epilepsy, and frontotemporal dementia. However, their precise role in disease pathology remains insufficiently understood. This study investigated the long-term effects of human anti-GluA3 antibodies (anti-GluA3 hIgGs) on neuronal morphology and function using primary rat hippocampal neurons. We found that long-term exposure to anti-GluA3 hIgGs leads to the delocalisation of GluA3- containing AMPARs at extrasynaptic sites. This molecular event is correlated to dendritic arbor reorganisation, characterised by increased complexity near the soma and progressive simplification in distal regions as well as an increase in the number of shorter dendrites and a corresponding loss of longer ones, thus suggesting altered dendritic pruning dynamics. The altered neuronal architecture was accompanied by an increase in the number of dendritic spines and a modification of their morphology, indicating relevant changes in synaptic connectivity. Functionally, anti-GluA3 hIgGs significantly enhanced NMDA receptor-mediated postsynaptic Ca2+ currents and increased nuclear levels of phosphorylated cAMP response element-binding protein (CREB), indicating altered signal transduction. Overall, our study provides critical insights into the role of anti-GluA3 hIgGs in disease and potentially identifies new therapeutic targets for pathological conditions where they are present.