NMDA1. Receptors and Anti-GluN Autoantibodies iIntroduction Central Disorders

1. Introduction

In recent years, the immune system (IS) emerged as a main player of the development and the functioning of the central nervous system (CNS). In physiological conditions, the IS and the CNS are in strict contact and cooperate to dictate the efficiency of synaptic transmission ^[1]. This cooperation, however, can be altered by concomitant pathological events, and its disorganization can reverberate negatively on synaptic plasticity. Accordingly, the etiopathogenesis of certain central neurological disorders has been associated to the anomalous overproduction of immunocompetent endogenous components, including autoantibodies recognizing neuronal cell-surface antigens, such as receptors and ion channels, most of which are involved in synaptic transmission [2,3]^[2][3]. Among these proteins, the NMDA receptors emerged as an important target with high immunogenic properties, pivotal to the immune-neuronal desynchronization.

NMDA receptors are ionotropic glutamate receptors composed of a tetrameric assembly of the obligatory GluN1 subunit with GluN2 (A-D) or the GluN3 (A-B) subunits or both[4] ^[4] . The stoichiometry of the subunit assembly defines the NMDA receptors’ properties, including the affinity of the receptor for the two main natural agonists (i.e., glutamate and glycine), as well as the gating and the ionic permeability of the associated channel [5–7]^[5][6][7]. NMDA receptors have a wide distribution in the central nervous system (CNS), where they locate in neurons, astrocytes, and oligodendrocytes. The role of the NMDARs in synaptic communication in physiological and in neurological conditions has been largely analyzed in the literature (see for instance [5–8]^[5][6][7][8]) and will not further be discussed.

During the last two decades, however, evidence accumulated showing that the NMDA receptor subunits, specifically the N terminus of the GluN1 subunit, possess immunogenic properties, and trigger the production of circulating anti-NMDA autoantibodies (specifically of anti-GluN1 autoantibodies), that concentrates in the serum and in the cerebrospinal fluid (CSF) of patients suffering from certain neurological disorders.

2. NMDA Receptors and Anti-GluN Autoantibodies in Central Disorders

2. NMDA Receptors and Anti-GluN Autoantibodies in Central Disorders

Autoantibodies against NMDA receptors were first identified in the CSF and in the serum of patients suffering from anti-NMDA receptor encephalitis, one of the most common forms of encephalitis. First associated with the presence of ovarian teratoma, this disease is nowadays associated also to ongoing viral infections and possibly other pathological conditions, that drive the autoimmune responses against the GluN subunits. In most cases, the triggering event(s) starts in the periphery, and then progresses centrally, leading to a robust intrathecal synthesis of anti-GluN autoantibodies [9] ^[9]. The disease progression depends on the production of the autoantibodies (which are specific markers of the pathology) and on the targeted NMDA receptor subunit [9–14] ^{[9][10][11][12][13][14]}, that in general is the GluN1 subunit (possibly because its immunogenic nature). The anti-GluN autoantibody binds the NH2 terminus of the protein and behaves as a receptor antagonist, reducing the receptor responsiveness towards the endogenous agonists (i.e. glycine, D-serine) and even favoring the internalization of the receptor [9–12]^{[9][10][11][12]}. In a whole, the autoantibody-induced adaptations reduce the number of the available NMDA receptors in plasmamembranes, then interfering with the glutamatergic transmission and sustaining synaptic desynchronization [8,11,15–17]^{[8][11][15][16][17]}. In line with the hypothesis, anti-NMDA receptor encephalitis is typified by neuropsychiatric symptoms (i.e. psychosis, cognitive impairment, anxiety, irritability, and autonomic disorders, but also seizures, catatonia, and coma) that are comparable to those elicited by the in vivo administration of non-competitive NMDA antagonists (i.e., ketamine or phencyclidine) and which largely recover after immunotherapy and/or plasmapheresis [18,19]. Corticosteroids alone or combined with intravenous IG administration or plasmapheresis are the first-line therapeutic approaches to manage this disease ^[19]. The timing of the intervention is crucial, since, in the case of delayed treatment, the symptoms can even worsen [15,20,21]^[15][20][21].

Notably, the production of autoantibodies targeting NMDA receptors is not an exclusive feature of the encephalitis, since anti-GluN1 autoantibodies also are detected in the serum and in the biological fluids of patients suffering from neurodegenerative disorders including Alzheimer’s (AD) and Parkinson’s disease (PD), as well as in neuropsychiatric diseases such dementia, epilepsy, and schizophrenia [21–23]^[21][22][23].

NMDA receptor autoantibodies were identified in the serum of a certain percentage of psychotic patients, in line with the proposed autoimmune origin for some idiopathic forms of schizophrenia [24–26] ^[24][25][26]. Despite these findings, the role of the anti-GluN autoantibodies in this pathology is however far to be elucidated and, in some cases, questioned, because of the variability of the anti-GluN autoantibody’s serum titer among individuals, which in some cases is of modest entity. Furthermore, the nature of the pathogenic Ig involved still is matter of discussion. Actually, in 10% of schizophrenic patients, the autoantibodies which target the GluN1A, and in some cases the GluN2B subunit, are mainly identified as IgA and IgM, and, to a lesser extent, as IgG [27] ^[27], despite only the IgG anti-NMDA receptor autoantibodies seems to be able to efficiently decrease the density of the synaptic and extra-synaptic NMDA receptors and/or alter their neuronal functions ^[28].

Autoantibodies targeting NMDA receptors also are associated with an atypical form of autoimmune dementia, that, differently from the classic neurodegenerative dementia, is characterized by psychiatric features, and which progression is slowed down by immunotherapy. In these patients, NMDA receptor autoantibodies consist of IgM, IgA, or IgG immunoglobulins that are detected in a significant percentage of symptomatic patients, but not in cognitively healthy controls [29,30] ^[29][30].

Lastly, anti-NMDA receptor autoantibodies were detected in the sera of AD and PD patients, but, due to their low prevalence, they are thought not to have a pathogenetic role per se, but rather to modulate the pathological phenotype ^[31].

3. NMDA Receptors and Anti-GluN Autoantibodies in Central Disorders: Unanswered Questions and New Perspective

3. NMDA Receptors and Anti-GluN Autoantibodies in Central Disorders: unanswered questions and new perspective

Despite the several observations that support the positive correlations linking the autoantibody overproduction and the progression of central neurological disorders, in recent years the exclusive pathogenic role of the anti-GluN autoantibodies has been questioned. Specifically, the finding that low levels of circulating anti-GluN1 autoantibodies also can be detected in the serum of healthy individuals, with no evident neuropsychiatric symptoms, was best interpreted by assuming that, beside the pathogenic activity, anti-GluN autoantibodies also could have a physiological role [32] ^[32]. The hypothesis is far to be addressed but the possibility that anti-NMDA autoantibodies could be protective in the CNS and increase the resilience to central injures (i.e.by reducing the excitotoxicity elicited by an excessive NMDA receptor activation) or even support the correct refinement and synaptic specialization during development (i.e. by driving the functional silencing of weak synapses to maintain synaptic plasticity) is attractive.

Another aspect so far poorly investigated is whether human anti-NMDA antibodies target indiscriminately all the NMDARs or, rather, if they specifically recognize and bind selected NMDAR subtypes in selected neuronal subpopulations (i.e. the glutamatergic instead of the GABAergic or the dopaminergic one, see [5,10]^[5][10]). Again, the question is compelling since, in the positive, the overproduction of anti-NMDA autoantibodies would provide a rationale for synaptic alterations that would subserve specific neuropathological phenotypes. For instance, anti-NMDA autoantibodies that specifically target NMDA heteroreceptors controlling GABA release (as indeed proven in the literature [167]^[16][17]) might be expected to reduce the central inhibitory GABAergic input onto the synaptic glutamatergic transmission, and to favor the schizophrenic phenotype, as proposed in the literature [24,33,34]^[24][33][34].

In this view, the possibility also should be investigated that the pathologic phenotype of patients suffering from the anti-NMDA receptor autoantibodies-mediated disorders might depend on so far unexplored structural and functional adaptation of the untargeted NMDA receptors as well as of non-NMDA receptors, colocalized and functionally associated to the targeted NMDA receptor. In other words, anti-GluN autoantibodies could alter the mechanism of metamodulation of synaptic transmission either in physiological or in pathological conditions, driving the efficiency of the synaptic networking [35,36]^[35][36]. It is the case of the dopaminergic type 1 receptors (D1Rs), which colocalize with the NMDA receptors and that are functionally regulated by human anti-NMDA receptor antibodies [37] ^[37].

All these points would deserve further investigations, for instance in preclinical in vitro and in vivo models, by using commercial anti GluN antibodies that, based on the available literature, efficiently reproduce the effects elicited by the human anti-GluN autoantibodies [9,16]^[9][16]. By using these approaches it will be possible to investigate: i) the mechanism(s) of internalization of the targeted NMDA receptors, ii) the responsiveness of different NMDARs to specific anti-GluN antibodies; iii) the functional adaptations of the untargeted NMDA receptors iv) the impact of of anti-GluN autoantibodies on colocalized non-NMDA receptors.

Besides permitting to define the cellular and molecular events that typify the course of autoimmune disorders, the results obtained in preclinical studies would also allow to check interventions for the management of the antibody-induced synaptic adaptations (see for instance the selective positive allosteric modulator of NMDA receptors that reverse the memory and synaptic alterations caused by CSF from patients with anti-NMDA receptor encephalitis in an animal model of passive transfer of antibodies ^[38]), providing new therapeutic intervention for CNS disorders.

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