TY - JOUR
T1 - Positive allosteric modulation as a potential therapeutic strategy in anti-NMDA receptor encephalitis
AU - Warikoo, Natasha
AU - Brunwasser, Samuel J.
AU - Benz, Ann
AU - Shu, Hong Jin
AU - Paul, Steven M.
AU - Lewis, Michael
AU - Doherty, James
AU - Quirk, Michael
AU - Piccio, Laura
AU - Zorumski, Charles F.
AU - Day, Gregory S.
AU - Mennerick, Steven
N1 - Funding Information:
This work was supported by a sponsored project agreement between Sage Pharmaceuticals and Washington UniversitySchoolofMedicine,andtheHarryWeaverNeuroscienceScholaroftheNationalMultipleSclerosisSociety (NMSS, JF 2144A2/1) to L.P. We thank Roberto Malinow and Elias Aizenman for making SEP-tagged and WT GluN subunits available and Anne Cross for help in obtaining control patient samples.
Publisher Copyright:
© 2018 the authors.
PY - 2018/3/28
Y1 - 2018/3/28
N2 - 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.
AB - 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.
KW - Autoimmune
KW - Glutamate
KW - NMDA receptor
KW - Schizophrenia
UR - http://www.scopus.com/inward/record.url?scp=85044714261&partnerID=8YFLogxK
U2 - 10.1523/JNEUROSCI.3377-17.2018
DO - 10.1523/JNEUROSCI.3377-17.2018
M3 - Article
C2 - 29476014
AN - SCOPUS:85044714261
SN - 0270-6474
VL - 38
SP - 3218
EP - 3229
JO - Journal of Neuroscience
JF - Journal of Neuroscience
IS - 13
ER -