Allosteric Modulation of NMDARs Reverses Patients' Autoantibody Effects in Mice

Abstract

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.

Positive Allosteric Modulation of NMDARs Prevents the Altered Surface Dynamics Caused by Patients' Antibodies

“… 6 , 7 In neurons exposed to patients' NMDAR-Ab, SGE-301 did not block the binding of antibodies but prevented the reduction of cell surface NMDAR without fully abrogating receptor internalization, suggesting that it might also change the surface dynamics. 7 , 8 The current findings confirm this hypothesis and, together with the reported effects of SGE-301 on ionotropic currents, 6 , 7 suggest a functional interplay between the state of the receptor and its membrane dynamics. Yet, the mechanism through which SGE-301 changes NMDAR diffusion remains unknown.…”

“… 6 Moreover, in mice infused with NMDAR-Ab, SGE-301 antagonized and reversed all pathogenic effects, including membrane receptor content and behavioral alterations. 7 , 8 Yet, the mechanisms underpinning these beneficial effects are not fully understood, leading to postulate that in addition to act as PAM, SGE-301 changes the NMDAR surface dynamics. Here, we address this hypothesis examining how SGE-301 modulates NMDAR membrane dynamics.…”

CPT1C is required for synaptic plasticity and oscillatory activity that supports motor, associative and non‐associative learning

“…For LTP experiments, the synaptic responses were evoked by single pulses applied on the Schaffer collateral pathway, and the intensity was adjusted to the strength necessary for evoking ∼40% of a maximal fEPSP. For induction of LTP, the stimulus intensity was also set at ∼40% of its asymptotic value, and animals were presented with a high‐frequency stimulation (HFS) session (Djebari et al., 2021) or, alternatively, a θ burst stimulation (TBS) session (Radosevic et al., 2022). The HFS protocol consisted of 100 Hz trains of 1s duration repeated five times with a 30 s inter‐train interval, and the TBS protocol consisted of 10 θ bursts of four pulses of 100 Hz with an interstimulus interval of 200 ms repeated seven times with 0.03 Hz.…”

Gene losses in the common vampire bat illuminate molecular adaptations to blood feeding

“…Increased cerebral 24S-hydroxycholesterol levels (mediated by overexpressing the 24S-hydroxycholesterol-synthesizing enzyme CYP46A1) improve spatial memory function in mice (85), whereas reduced 24S-hydroxycholesterol levels (mediated by deleting CYP46A1) cause deficiencies in hippocampal long-term potentiation and impaired learning and memory function (86). Consistent with 24S-hydroxycholesterol exerting a direct effect on NMDAR activity and cognitive function, administration of 24S-hydroxycholesterol analogs reversed an induced reduction in synaptic NMDAR frequency and function, long-term potentiation, and memory formation in mice (87). NMDAR activity also exerts a strong influence on social behavior, as NMDAR agonists improve social behavior in rodents, whereas antagonists impair it (88).…”