Anti-AMPA Receptor Autoantibodies Reduce Excitatory Currents in Rat Hippocampal Neurons

Area of Science:

• Neuroscience
• Immunology
• Molecular Biology

Background:

• Autoantibodies (Aabs) targeting GluR3 subunits of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) are implicated in autoimmune encephalopathy.
• The precise impact of these Aabs on neuronal excitability remains unclear, despite evidence of their binding to specific GluR3 regions.

Purpose of the Study:

• To investigate the functional consequences of anti-AMPAR autoantibodies on neuronal excitability.
• To determine if anti-GluR3 Aabs disrupt synaptic function relevant to autoimmune diseases.

Main Methods:

• Generation of novel anti-AMPAR autoantibodies using GLUR3B peptides based on immunogenic epitopes.
• Confirmation of antibody binding and specificity via ELISA, immunocytochemistry, and Western blot.
• Assessment of functional effects on excitatory postsynaptic currents (EPSCs) in primary hippocampal neurons using whole-cell patch-clamp electrophysiology.

Main Results:

• Application of anti-AMPAR Aabs significantly reduced the frequency of spontaneous and miniature EPSCs in hippocampal neurons.
• Both acute (10-30 min) and longer-term (24 h) exposure to Aabs demonstrated inhibitory effects on synaptic activity.
• The observed reduction in EPSC frequency indicates a direct impact on neuronal excitability at the synaptic level.

Conclusions:

• Anti-AMPAR autoantibodies targeting GluR3 subunits exert inhibitory effects on neuronal excitability.
• These synaptic disruptions may lead to an imbalance between excitation and inhibition within neural networks.
• The findings provide insights into the pathogenic mechanisms of autoimmune encephalopathies involving anti-AMPAR antibodies.