Positive Allosteric Modulation as a Potential Therapeutic Strategy in Anti-NMDA Receptor Encephalitis

The Journal of Neuroscience : the Official Journal of the Society for Neuroscience
Natasha WarikooSteven Mennerick

Abstract

N-methyl-d-aspartate receptors (NMDARs) are ionotropic glutamate receptors important for synaptic plasticity, memory, and neuropsychiatric 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 NMDAR...Continue Reading

Associated Clinical Trials

Citations

Feb 5, 2019·The Journal of Clinical Investigation·Christian GeisJosep Dalmau
Oct 30, 2019·Current Topics in Medicinal Chemistry·Paul J Goldsmith
Aug 25, 2020·Brain : a Journal of Neurology·Francesco MannaraJosep Dalmau
Dec 24, 2018·Frontiers in Neuroscience·Daniel M ChenSteven Mennerick
Nov 26, 2020·Expert Opinion on Therapeutic Targets·Josefine SellChristian Geis
Jun 4, 2021·Neuropharmacology·Lonnie P WollmuthLaurent Groc
Feb 6, 2019·Journal of Medicinal Chemistry·Quinn CoughlinDario Doller

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