Positive allosteric modulation as a potential therapeutic strategy in anti-NMDA receptor encephalitis

Natasha Warikoo, Samuel J. Brunwasser, Ann Benz, Hong-Jin Shu, Steven M. Paul, Michael Lewis, James Doherty, Michael Quirk, Laura Piccio, Charles F. Zorumski, Gregory S. Day and Steven Mennerick. Journal of Neuroscience, Volume 38, Issue 13, 28 March 2018, Pages 3218-3229 Read More

Abstract

N-methyl-D-aspartate receptors (NMDARs) are ionotropic glutamate receptors important for synaptic plasticity, memory, and neuro-psychiatric health. NMDAR hypofunction contributes to multiple disorders, including anti-NMDAR encephalitis (NMDARE), an autoimmune disease of the CNS associated with GluN1 antibody-mediated NMDAR internalization. Here we characterize the functional/ pharmacological consequences of exposure to CSF from female human NMDARE patients on NMDAR function, and we characterize the effects of intervention with recently described positive allosteric modulators (PAMs) of NMDARs. Incubation (48 h) of rat hippocampal neurons of both sexes in confirmed NMDARE patient CSF, but not control CSF, attenuated NMDA-induced current. Residual NMDAR function was characterized by lack of change in channel open probability, indiscriminate loss of synaptic and extrasynaptic NMDARs, and indiscriminate loss of GluN2B-containing and GluN2B-lacking NMDARs. NMDARs tagged with N-terminal pHluorin fluorescence demonstrated loss of surface receptors. Thus, function of residual NMDARs following CSF exposure was indistinguishable from baseline, and deficits appear wholly accounted for by receptor loss. Coapplication of CSF and PAMs of NMDARs (SGE-301 or SGE-550, oxysterol-mimetic) for 24 h restored NMDAR function following 24 h incubation in patient CSF. Curiously, restoration of NMDAR function was observed despite washout of PAMs before electrophysiological recordings. Subsequent experiments suggested that residual allosteric potentiation of NMDAR function explained the persistent rescue. Further studies of the pathogenesis of NMDARE and intervention with PAMs may inform new treatments for NMDARE and other disorders associated with NMDAR hypofunction. © 2018 the authors.

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Posted on April 17, 2018
Posted in: Axon Injury & Repair, Clocks & Sleep, HPAN, Neurodegeneration, Publications Authors: , , ,