Mechanisms underlying autoimmune synaptic encephalitis leading to disorders of memory, behavior and cognition: insights from molecular, cellular and synaptic studies

Abstract

Recently, several novel, potentially lethal and treatment-responsive syndromes that affect hippocampal and cortical function have been shown to be associated with auto-antibodies against synaptic antigens, notably glutamate or GABA-B receptors. Patients with these auto-antibodies, sometimes associated with teratomas and other neoplasms, present with psychiatric symptoms, seizures, memory deficits and decreased levels of consciousness. These symptoms often improve dramatically after immunotherapy or tumor resection. Here we review studies of the cellular and synaptic effects of these antibodies in hippocampal neurons in vitro and preliminary work in rodent models. Our work suggests that patient antibodies lead to rapid and reversible removal of neurotransmitter receptors from synaptic sites, leading to changes in synaptic and circuit function that in turn are likely to lead to behavioral deficits. We also discuss several of the many questions raised by these and related disorders. Determining the mechanisms underlying these novel anti-neurotransmitter receptor encephalopathies will provide insights into the cellular and synaptic bases of the memory and cognitive deficits that are hallmarks of these disorders, and potentially suggest avenues for therapeutic intervention.

Figure 1. Mechanisms involved in the presence of antibodies in the central nervous system

A – B: In a subset of anti-NMDA receptor encephalitis patients, an immune response is initiated against neuronal antigens expressed by an ovarian teratoma or another tumor (A). In another subset of patients, the immunological trigger is unknown (B). The ectopic expression of NMDA receptors by a tumor or other mechanisms (e.g., molecular mimicry) break down immune tolerance by a sequence of mechanisms including antigen presentation by T or dendritic cells generating memory B-cells (1) and antibody-producing plasma cells (2). Systemically synthesized antibodies can bind to NMDA receptors present in the tumor and a disrupted or leaky blood brain barrier (BBB) (4). Disruption of the BBB is likely to occur early in the disease process. In addition, memory B-cells (likely also activated T-cells) that are able to cross a normal BBB (5), will undergo re-stimulation (resident antigen presenting cells or T-cells, 6), antigen-driven affinity maturation, clonal expansion, and differentiation into NMDA receptor antibody-secreting plasma cells (7). Antibodies produced within the CNS by plasma cells (8) or reaching the CNS by BBB disruption (4) bind to extracellular epitopes of NMDA receptor (9) causing subsequent dysfunction and internalization (see Figure 2).

Figure 2. Mechanisms underlying cellular and synaptic effects of anti-NMDA receptor antibodies

A-C: AMPA and NMDA receptors are localized in the postsynaptic membrane and are clustered at the postsynaptic density (A). Patient antibodies in the CNS bind selectively to NMDA receptors at the synapse as well as extrasynaptic receptors. This binding leads to receptor cross-linking (B). NMDA receptors that have been bound and cross-linked by antibodies are internalized, resulting in a decrease of surface, synaptically localized NMDA receptors. Other synaptic components, such as postsynaptic AMPA receptor clusters, PSD-95, as well as presynaptic terminals, dendrite branches, dendritic spines and cell viability, are unaffected (C). Thus patient anti-NMDA receptor antibodies lead to a rapid, selective excision of NMDA receptors from neuronal membranes. This effect is titer-dependent and reverses after antibody titers are reduced (not shown). D-E: Rodent cultured neurons treated with control CSF or patient's CSF for 3 days, and subsequently stained for postsynaptic NR1 to label NMDA receptor clusters, VGlut to label presynaptic sites, and PSD-95 as a postsynaptic marker. Note that patient's CSF cause a decrease in dendritic NR1 cluster density, while VGlut and PSD-95 cluster density remain unchanged. F-G: Whole-cell patch recordings of miniature excitatory postsynaptic currents (mEPSCs), which consist of a fast AMPA receptor-mediated component and a later, slower NMDA receptor-mediated component that is APV sensitive. Compared to neurons incubated with CFS control (F), those treated with CSF from a patient with NMDA receptor antibodies show a selective loss of the APV-sensitive NMDA receptor component (E).