Allosteric Modulation of NMDARs Reverses Patients' Autoantibody Effects in Mice

Background and ObjectivesTo demonstrate that an analog (SGE-301) of a brain-derived cholesterol metabolite, 24(S)-hydroxycholesterol, which is a selective positive allosteric modulator (PAM) of NMDA receptors (NMDARs), is able to reverse the memory and synaptic alterations caused by CSF from patients with anti-NMDAR encephalitis in an animal model of passive transfer of antibodies.MethodsFour groups of mice received (days 1–14) patients' or controls' CSF via osmotic pumps connected to the cerebroventricular system and from day 11 were treated with daily subcutaneous injections of SGE-301 or vehicle (no drug). Visuospatial memory, locomotor activity (LA), synaptic NMDAR cluster density, hippocampal long-term potentiation (LTP), and paired-pulse facilitation (PPF) were assessed on days 10, 13, 18, and 26 using reported techniques.ResultsOn day 10, mice infused with patients' CSF, but not controls' CSF, presented a significant visuospatial memory deficit, reduction of NMDAR clusters, and impairment of LTP, whereas LA and PPF were unaffected. These alterations persisted until day 18, the time of maximal deficits in this model. In contrast, mice that received patients' CSF but from day 11 were treated with SGE-301 showed memory recovery (day 13), and on day 18, all paradigms (memory, NMDAR clusters, and LTP) had reversed to values similar to those of controls. On day 26, no differences were observed among experimental groups.DiscussionAn oxysterol biology-based PAM of NMDARs is able to reverse the synaptic and memory deficits caused by CSF from patients with anti-NMDAR encephalitis. These findings suggest a novel adjuvant treatment approach that deserves future clinical evaluation.

Download Full-text

Differentially Altered NMDAR Dependent and Independent Long-Term Potentiation in the CA3 Subfield in a Model of Anti-NMDAR Encephalitis

Frontiers in Synaptic Neuroscience ◽

10.3389/fnsyn.2018.00026 ◽

2018 ◽

Vol 10 ◽

Cited By ~ 8

Author(s):

Roman Blome ◽

Willi Bach ◽

Xiati Guli ◽

Katrin Porath ◽

Tina Sellmann ◽

...

Keyword(s):

Long Term Potentiation ◽

Nmdar Encephalitis ◽

Term Potentiation

Download Full-text

[P4-036]: THE NOVEL AMPA RECEPTOR POSITIVE ALLOSTERIC MODULATOR S 47445 RESCUES IN VIVO CA3-CA1 LONG-TERM POTENTIATION AND STRUCTURAL SYNAPTIC CHANGES IN MIDDLE-AGED MICE

Alzheimer s & Dementia ◽

10.1016/j.jalz.2017.06.1900 ◽

2017 ◽

Vol 13 (7S_Part_26) ◽

pp. P1270-P1270

Author(s):

Sylvie Bretin ◽

Albert Giralt ◽

María Ángeles Gómez-Climent ◽

Rafael Alcalá ◽

Jose Maria Delgado-Garcia ◽

...

Keyword(s):

Ampa Receptor ◽

Long Term Potentiation ◽

Allosteric Modulator ◽

The Novel ◽

Positive Allosteric Modulator ◽

Aged Mice ◽

Term Potentiation ◽

Synaptic Changes

Download Full-text

Allosteric modulation of NMDA receptors prevents the antibody effects of patients with anti-NMDAR encephalitis

Brain ◽

10.1093/brain/awaa195 ◽

2020 ◽

Vol 143 (9) ◽

pp. 2709-2720 ◽

Cited By ~ 2

Author(s):

Francesco Mannara ◽

Marija Radosevic ◽

Jesús Planagumà ◽

David Soto ◽

Esther Aguilar ◽

...

Keyword(s):

Subcutaneous Administration ◽

Long Term Potentiation ◽

Memory Deficit ◽

Cultured Neurons ◽

Synthetic Analogue ◽

Systemic Delivery ◽

Nmdar Encephalitis ◽

Term Potentiation ◽

Antibody Effects

Abstract Anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis is an immune-mediated disease characterized by a complex neuropsychiatric syndrome in association with an antibody-mediated decrease of NMDAR. About 85% of patients respond to immunotherapy (and removal of an associated tumour if it applies), but it often takes several months or more than 1 year for patients to recover. There are no complementary treatments, beyond immunotherapy, to accelerate this recovery. Previous studies showed that SGE-301, a synthetic analogue of 24(S)-hydroxycholesterol, which is a potent and selective positive allosteric modulator of NMDAR, reverted the memory deficit caused by phencyclidine (a non-competitive antagonist of NMDAR), and prevented the NMDAR dysfunction caused by patients’ NMDAR antibodies in cultured neurons. An advantage of SGE-301 is that it is optimized for systemic delivery such that plasma and brain exposures are sufficient to modulate NMDAR activity. Here, we used SGE-301 to confirm that in cultured neurons it prevented the antibody-mediated reduction of receptors, and then we applied it to a previously reported mouse model of passive cerebroventricular transfer of patient’s CSF antibodies. Four groups were established: mice receiving continuous (14-day) infusion of patients’ or controls’ CSF, treated with daily subcutaneous administration of SGE-301 or vehicle (no drug). The effects on memory were examined with the novel object location test at different time points, and the effects on synaptic levels of NMDAR (assessed with confocal microscopy) and plasticity (long-term potentiation) were examined in the hippocampus on Day 18, which in this model corresponds to the last day of maximal clinical and synaptic alterations. As expected, mice infused with patient’s CSF antibodies, but not those infused with controls’ CSF, and treated with vehicle developed severe memory deficit without locomotor alteration, accompanied by a decrease of NMDAR clusters and impairment of long-term potentiation. All antibody-mediated pathogenic effects (memory, synaptic NMDAR, long-term potentiation) were prevented in the animals treated with SGE-301, despite this compound not antagonizing antibody binding. Additional investigations on the potential mechanisms related to these SGE-301 effects showed that (i) in cultured neurons SGE-301 prolonged the decay time of NMDAR-dependent spontaneous excitatory postsynaptic currents suggesting a prolonged open time of the channel; and (ii) it significantly decreased, without fully preventing, the internalization of antibody-bound receptors suggesting that additional, yet unclear mechanisms, contribute in keeping unchanged the surface NMDAR density. Overall, these findings suggest that SGE-301, or similar NMDAR modulators, could potentially serve as complementary treatment for anti-NMDAR encephalitis and deserve future investigations.

Download Full-text