Abstract
The role of autoimmunity in central nervous system (CNS) disorders is rapidly expanding. In the last twenty years, different types of autoantibodies targeting subunits of ionotropic glutamate receptors have been found in a variety of patients affected by brain disorders. Several of these antibodies are directed against NMDA receptors (NMDAR), mostly in autoimmune encephalitis, whereas a growing field of research has identified antibodies against AMPA receptor (AMPAR) subunits in patients with different types of epilepsy or frontotemporal dementia. Several in vitro and in vivo studies performed in the last decade have dramatically improved our understanding of the molecular and functional effects induced by both NMDAR and AMPAR autoantibodies at the excitatory glutamatergic synapse and, consequently, their possible role in the onset of clinical symptoms. In particular, the method by which autoantibodies can modulate the localization at synapses of specific target subunits leading to functional impairments and behavioral alterations has been well addressed in animal studies. Overall, these preclinical studies have opened new avenues for the development of novel pharmacological treatments specifically targeting the synaptic activation of ionotropic glutamate receptors.
Highlights
Autoimmunity is an emerging field of research that can potentially play a key role in a better understanding of different types of Central Nervous System (CNS) disorders [1,2,3,4,5].Autoantibodies that target neuronal surface proteins, including neurotransmitter receptors, have been described mainly in association with autoimmune encephalitis, which prominently features psychiatric symptoms, cognitive impairment, and seizures [6]
Autoantibodies directed against subunits of both N-methyl-D-aspartate receptor (NMDAR) and α-amino3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) seem to be among the most diffuse, abundant, and clinically relevant autoimmune antibodies identified in the last decades [4]
The presence of anti-GluA3 Abs in frontotemporal dementia (FTD) patients corroborates other evidence claiming a possible role of AMPARs in FTD pathogenesis: The hyperexcitability of AMPARs contributed to neurodegeneration [72]; social deficits were accompanied by a change in AMPAR composition in an animal model of FTD [72]; frontal cortex and human-induced pluripotent stem cells of behavioral-variant FTD patients showed changes in AMPARs [73]; and the physiological release of Tau protein was mediated by AMPARs [74]
Summary
Autoimmunity is an emerging field of research that can potentially play a key role in a better understanding of different types of Central Nervous System (CNS) disorders [1,2,3,4,5]. The potential role of these autoantibodies in different forms of chronic disorders, such as epilepsy, schizophrenia, and dementia, is of increasing interest [1,3]. We will review clinical and preclinical studies that have hallowed the characterization of most of their pathological roles in the brain, and the identification of different molecular mechanisms by which they can affect the synaptic localization and function of the target receptor and, impair excitatory signaling in affected brain circuits (Table 1). AMPAR internalization, spine loss internalization, synaptic plasticity impairment, memory deficits, depressive-like behavior internalization, reduced intracortical facilitation
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