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Novel neuroactive steroids as positive allosteric modulators of NMDA receptors: mechanism, site of action, and rescue pharmacology on GRIN variants associated with neurological conditions

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Abstract

N-methyl-D-aspartate receptors (NMDARs) play vital roles in normal brain functions (i.e., learning, memory, and neuronal development) and various neuropathological conditions, such as epilepsy, autism, Parkinson’s disease, Alzheimer’s disease, and traumatic brain injury. Endogenous neuroactive steroids such as 24(S)-hydroxycholesterol (24(S)-HC) have been shown to influence NMDAR activity, and positive allosteric modulators (PAMs) derived from 24(S)-hydroxycholesterol scaffold can also enhance NMDAR function. This study describes the structural determinants and mechanism of action for 24(S)-hydroxycholesterol and two novel synthetic analogs (SGE-550 and SGE-301) on NMDAR function. We also show that these agents can mitigate the altered function caused by a set of loss-of-function missense variants in NMDAR GluN subunit-encoding GRIN genes associated with neurological and neuropsychiatric disorders. We anticipate that the evaluation of novel neuroactive steroid NMDAR PAMs may catalyze the development of new treatment strategies for GRIN-related neuropsychiatric conditions.

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Data availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

Abbreviations

24(S)-HC:

24(S)-hydroxycholesterol

7-CKA:

7-Chlorokynurenic acid

ABD:

Agonist binding domain

AP-5:

D,L-2-Amino-5-phosphonovalerate

ASD:

Autism spectrum disorder

ATD:

Amino terminal domain

CTD:

Carboxyl terminal domain

EPSP:

Excitatory postsynaptic potential

LBD:

Ligand binding domain

LoF:

Loss-of-function

MNSs:

Medium spiny neurons

MTSEA:

2-Aminoethyl methanethiosulfonate hydrobromide

NAS:

Neuroactive steroids

NGS:

Next-generation sequencing

NMDAR:

N-Methyl-d-aspartate receptor

NTD:

N-terminal domain

PAM:

Positive allosteric modulator

TEVC:

Two-electrode voltage clamp

TMD:

Transmembrane domain (M1-4)

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Acknowledgements

This work was supported by NINDS NS111619 (S.F.T.), by NICHD HD082373 (H.Y.), and by a grant from Sage Therapeutics to Emory University (H.Y.). We thank Jennifer Bain for helpful comments, Dr. TJ Murphy for his excellent advice on statistical analyses, and Jing Zhang for her excellent technical assistance.

Funding

This work was supported by Eunice Kennedy Shriver National Institute of Child Health and Human Development (HD082373), National Institute of Neurological Disorders and Stroke (NS111619), Sage Therapeutics.

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Author notes

  1. Weiting Tang

    Present address: Department of Neurology, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China

  2. Jin Zhang

    Present address: Department of Neurology, The First Hospital of Shanxi Medical University, Taiyuan, 030001, Shanxi, China

  3. Rui Song

    Present address: Department of Neurology, Qilu Hospital of Shandong University, Jinan, 250012, Shandong, China

  4. Yuchen Xu

    Present address: Department of Neurology, The First Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China

  5. Weiting Tang and Jacob T. Beckley contributed equally to this work.

Authors and Affiliations

  1. Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, GA, 30322, USA

    Weiting Tang, Jin Zhang, Rui Song, Yuchen Xu, Sukhan Kim, Eva Sarai Diaz, Scott J. Myers, Stephen F. Traynelis & Hongjie Yuan

  2. Sage Therapeutics Inc, Cambridge, MA, 02142, USA

    Jacob T. Beckley, Michael C. Quirk, Albert J. Robichaud, James J. Doherty & Michael A. Ackley

  3. Center for Functional Evaluation of Rare Variants (CFERV), Emory University School of Medicine, Atlanta, GA, 30322, USA

    Sukhan Kim, Scott J. Myers, Stephen F. Traynelis & Hongjie Yuan

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Contributions

H.Y., S.F.T., J.T.B., S.J.M., M.A.A., and J.J.D. designed the experiments and analyzed the data. W.T., R.S., Y.X., S.K., S.J.M., E.S.D., J.Z., and H.Y. performed biological experiments. All authors discussed the results and implications. All authors wrote the manuscript and read and approved the final manuscript.

Corresponding authors

Correspondence to Stephen F. Traynelis or Hongjie Yuan.

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Conflict of interest

S.F.T. is a member of the SAB for Eumentis Therapeutics and Sage Therapeutics, is a member of the Medical Advisory Board for the GRIN2B Foundation and the CureGRIN Foundation, is an advisor to GRIN Therapeutics and Combined Brain, is co-founder of NeurOp Inc. and AgriThera Inc., and is a member of the Board of Directors of NeurOp Inc. H.Y. is PI on a research grant from Sage Therapeutics to Emory University School of Medicine. S.J.M. is PI on a research grant from GRIN Therapeutics to Emory University School of Medicine. S.F.T., S.J.M., and H.Y. are co-inventors on Emory University-owned Intellectual Property that includes allosteric modulators of NMDA receptor function. M.A.A., J.T.B., J.J.D., M.C.Q., and A.J.R. are employees of Sage Therapeutics.

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Tang, W., Beckley, J.T., Zhang, J. et al. Novel neuroactive steroids as positive allosteric modulators of NMDA receptors: mechanism, site of action, and rescue pharmacology on GRIN variants associated with neurological conditions. Cell. Mol. Life Sci. 80, 42 (2023). https://doi.org/10.1007/s00018-022-04667-7

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