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Cellular plasticity induced by anti–α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid (AMPA) receptor encephalitis antibodies
Author(s) -
Peng Xiaoyu,
Hughes Ethan G.,
Moscato Emilia H.,
Parsons Thomas D.,
Dalmau Josep,
BaliceGordon Rita J.
Publication year - 2015
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.24293
Subject(s) - ampa receptor , neurotransmission , neuroscience , nmda receptor , synaptic plasticity , inhibitory postsynaptic potential , glutamatergic , biology , chemistry , glutamate receptor , receptor , biochemistry
Objective Autoimmune‐mediated anti–α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid receptor (AMPAR) encephalitis is a severe but treatment‐responsive disorder with prominent short‐term memory loss and seizures. The mechanisms by which patient antibodies affect synapses and neurons leading to symptoms are poorly understood. Methods The effects of patient antibodies on cultures of live rat hippocampal neurons were determined with immunostaining, Western blot, and electrophysiological analyses. Results We show that patient antibodies cause a selective decrease in the total surface amount and synaptic localization of GluA1‐ and GluA2‐containing AMPARs, regardless of receptor subunit binding specificity, through increased internalization and degradation of surface AMPAR clusters. In contrast, patient antibodies do not alter the density of excitatory synapses, N‐methyl‐D‐aspartate receptor (NMDAR) clusters, or cell viability. Commercially available AMPAR antibodies directed against extracellular epitopes do not result in a loss of surface and synaptic receptor clusters, suggesting specific effects of patient antibodies. Whole‐cell patch clamp recordings of spontaneous miniature postsynaptic currents show that patient antibodies decrease AMPAR‐mediated currents, but not NMDAR‐mediated currents. Interestingly, several functional properties of neurons are also altered: inhibitory synaptic currents and vesicular γ‐aminobutyric acid transporter (vGAT) staining intensity decrease, whereas the intrinsic excitability of neurons and short‐interval firing increase. Interpretation These results establish that antibodies from patients with anti‐AMPAR encephalitis selectively eliminate surface and synaptic AMPARs, resulting in a homeostatic decrease in inhibitory synaptic transmission and increased intrinsic excitability, which may contribute to the memory deficits and epilepsy that are prominent in patients with this disorder. Ann Neurol 2015;77:381–398