Cellular and Synaptic Mechanisms of Anti-NMDA Receptor Encephalitis

Abstract

We recently described a severe, potentially lethal, but treatment-responsive encephalitis that associates with autoantibodies to the NMDA receptor (NMDAR) and results in behavioral symptoms similar to those obtained with models of genetic or pharmacologic attenuation of NMDAR function. Here, we demonstrate that patients' NMDAR antibodies cause a selective and reversible decrease in NMDAR surface density and synaptic localization that correlates with patients' antibody titers. The mechanism of this decrease is selective antibodymediated capping and internalization of surface NMDARs, as Fab fragments prepared from patients' antibodies did not decrease surface receptor density, but subsequent cross-linking with anti-Fab antibodies recapitulated the decrease caused by intact patient NMDAR antibodies. Moreover, whole-cell patch-clamp recordings of miniature EPSCs in cultured rat hippocampal neurons showed that patients' antibodies specifically decreased synaptic NMDAR-mediated currents, without affecting AMPA receptor-mediated currents. In contrast to these profound effects on NMDARs, patients' antibodies did not alter the localization or expression of other glutamate receptors or synaptic proteins, number of synapses, dendritic spines, dendritic complexity, or cell survival. In addition, NMDAR density was dramatically reduced in the hippocampus of female Lewis rats infused with patients' antibodies, similar to the decrease observed in the hippocampus of autopsied patients. These studies establish the cellular mechanisms through which antibodies of patients with anti-NMDAR encephalitis cause a specific, titer-dependent, and reversible loss of NMDARs. The loss of this subtype of glutamate receptors eliminates NMDAR-mediated synaptic function, resulting in the learning, memory, and other behavioral deficits observed in patients with anti-NMDAR encephalitis.

NMDAR encephalitis: passive transfer from man to mouse by a recombinant antibody

“…Although anti‐NMDAR antibodies are mainly of the complement‐activating IgG1 and IgG3 subtypes, complement deposition was not detected in brain biopsy specimens from treatment‐naïve patients with anti‐NMDAR encephalitis, probably due to the low levels of complement present in CSF and relative preservation of the blood–brain barrier (BBB) 7, 13. Consistently, anti‐NMDAR IgG antibodies did not reduce the number of synapses, dendritic spines, dendritic complexity, or cell survival in cultured rat hippocampal neurons,9 and neuronal damage was sparse in brain biopsy specimens 13, 14. Passive infusion of patients' CSF into the cerebroventricular system of mice via osmotic minipumps induced reversible memory impairment and behavioral changes consistent with symptoms found in patients with anti‐NMDAR encephalitis in vivo 15…”

“…These effects are associated with a disruption of the normal interaction between the NMDAR and Ephrin‐B2 (EphB2) receptor at the synapse 10, 11. Consistently, anti‐NMDAR antibodies selectively decreased NMDAR‐mediated miniature excitatory postsynaptic currents (mEPSC) without affecting α ‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid receptor (AMPA‐R)‐mediated mEPSCs in cultured rat hippocampal neurons 8, 9. Once internalized, antibody‐bound NMDARs traffic through both recycling endosomes and lysosomes, but do not induce compensatory changes in glutamate receptor gene expression 8, 12.…”

“…In vitro, IgG antibodies contained in serum/CSF have been shown to bind to the N368/G369 region of the GluN1 subunit of NMDARs and reversibly decrease postsynaptic NMDAR surface density and synaptic localization in inhibitory as well as excitatory cultured rat hippocampal neurons by selective antibody‐mediated cross‐linking and internalization 8, 9. These effects are associated with a disruption of the normal interaction between the NMDAR and Ephrin‐B2 (EphB2) receptor at the synapse 10, 11.…”

A case report: anti-NMDA receptor encephalitis

“…NMDARs play a central role in synaptic transmission helping to modulate human memory, cognition, and learning and have been implicated in neural plasticity [2]. Activity of the NMDAR is affected not only by several exogenous substances, including PCP, ketamine, and ethanol, but also endogenous brain-immune interactions that can have tremendous clinical consequence.…”

“…The structure of the NMDAR is composed primarily of ubiquitous NR1 and NR2 subunits [2]. The antibodies in anti-NMDAR encephalitis are directed against an epitope found on the NR1 subunit primarily in the frontotemporal and hippocampal regions likely owing to the high density of these receptors in these regions [3,4].…”