A more recent study confirmed that GluA2 autoantibodies promote receptor internalization and a consequent decrease in synaptic GluA2-containing AMPARs [47]. 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. Keywords:autoimmunity, glutamate, brain disorders, excitatory synapse == 1. Introduction == 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]. However, the potential role of these autoantibodies in different forms of chronic disorders, such as epilepsy, schizophrenia, and dementia, is usually of increasing interest [1,3]. Autoantibodies directed against subunits of both N-methyl-D-aspartate receptor (NMDAR) and -amino-3-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]. 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 Methscopolamine bromide receptor and, consequently, impair excitatory signaling in affected brain circuits (Table 1). == Table 1. == Clinical and preclinical effects of NMDAR and AMPAR autoantibodies. == 2. NMDAR Autoantibodies: Anti-GluN1 == NMDARs are tetramers composed of two obligatory GluN1 subunits, associated with two regulatory subunits of GluN2-type (GluN2A-D) or GluN3-type (GluN3A-B), Methscopolamine bromide whose expression varies in different brain regions and developmental periods [7]. NMDARs are ligand- and voltage-gated ionotropic glutamate receptors that regulate Ca2+influx. In addition, NMDAR is blocked by Mg2+at resting potential, and this inhibition is usually removed by AMPA-dependent depolarization. Accordingly, NMDARs are considered a postsynaptic coincidence detector linking presynaptic glutamate release and postsynaptic depolarization [8]. Autoantibodies targeting NMDAR have Methscopolamine bromide been described in anti-NMDAR encephalitis (NMDARE), an Rabbit Polyclonal to WEE2 autoimmune synaptic brain disorder characterized by the presence of IgG antibodies that recognize the extracellular N368/G369 region domain of Methscopolamine bromide the GluN1 obligatory subunit of NMDAR [9]. Adult patients affected by anti-NMDAR encephalitis present with psychosis, behavioral disorders, or confusion, as well as other symptoms such as seizures, movement disorders, sleep disorders, and irritability [10,11]. Importantly, anti-NMDAR encephalitis is considered the most common form of autoimmune encephalitis, and it accounts for about 4% of patients with any form of encephalitis [12]. The clinical features of autoimmune encephalitis are frequently preceded by symptoms suggesting an infectious process, and it has been exhibited that a herpes simplex contamination can trigger autoimmune encephalitis with neurological worsening [13]. Although viral infections might not directly trigger the diseases onset, they may induce the breakdown of the bloodbrain barrier and cause a further inflammation reaction, as well as epitope spreading and chronic activation of innate immunity actors [14]. In the same view, a few reports have suggested a link between viral SARS-COV-2 contamination and anti-NMDAR encephalitis, but a definite pathogenetic role has not been postulated [15,16]. Furthermore, previous studies have suggested that vaccinations such as the H1N1 vaccine, tetanus/diphtheria/pertussis and polio vaccine, and Japanese encephalitis vaccine, might induce autoimmune encephalitis [17]. Even if early studies identified the presence of anti-GluN1 antibodies to ovarian teratoma [18], they can be associated also with non-paraneoplastic forms and other causes including viral infections. Moreover, although some studies reported the presence of anti-NMDAR IgM and IgA in about 10% of patients affected by schizophrenia, the same type of antibodies were also identified in patients with other brain disorders, including dementia, stroke, and Parkinsons disease, thus suggesting the absence of specificity and, therefore, a reduced clinical relevance [19,20,21]. Moreover, conversely to what was clearly exhibited for anti-NMDAR IgG found in anti-NMDAR encephalitis, it seems that anti-NMDAR IgM and IgA associated with other diseases Methscopolamine bromide do not alter NMDAR synaptic function [22]. Finally, between 4% and 7.5% of patients with anti-NMDAR encephalitis have concurrent glial or neuronal-surface antibodies, with the most frequent association being with myelin oligodendrocyte glycoprotein (MOG) or aquaporin 4 (AQP4) antibodies, which result in overlapping anti-NMDAR encephalitis with demyelinating disorders [23,24]. The presence of these autoimmune associations has clinical implications, conferring additional clinical and radiologic features to anti-NMDAR encephalitis and influencing prognosis and treatment approaches [23]. Since the first report in 2007 [18], several studies have been performed not only related to the clinical management of the disease, but also to address the precise molecular mechanisms by which the presence of anti-GluN1 antibodies induces pathological alterations of the glutamatergic.