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Acute rapamycin treatment reveals distinct mechanisms of dysfunction in a maternal inflammation mouse model.

Overview

Authors: JE Le Belle1,2,3, M. C. Condro1, C. Cepeda1,4, KD Oikonomou1, K. Tessema1, L. Dudley1, J. Schoenfield2, R. Kawaguchi1, D. Geschwind1,5,6,7, AJ Silva4,7,8,9,10, Z. Zhang11, K. Shokat11, NG Harris2,3,7, HI Kornblum1,3,4,7,12,13
ORCID iDs: JE Le Belle, K. Tessema, J. Schoenfield, R. Kawaguchi, D. Geschwind, Z. Zhang, K. Shokat, NG Harris, HI Kornblum
13 affiliations
  1. Semel Institute for Neuroscience & Human Behavior, Department of Psychiatry, David Geffen School of Medicine, UCLA,Los Angeles, CA USA
  2. The UCLA Brain Injury Research Center, Department of Neurosurgery, David Geffen School of Medicine, UCLA,Los Angeles, CA USA
  3. UCLA Intellectual and Developmental Disabilities Research Center, Semel Institute, Department of Psychiatry, David Geffen School of Medicine, UCLA,Los Angeles, CA USA
  4. Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, UCLA,Los Angeles, CA USA
  5. Program in Neurogenetics, Department of Neurology, David Geffen School of Medicine, UCLA,Los Angeles, CA USA
  6. Department of Human Genetics, UCLA,Los Angeles, CA USA
  7. Brain Research Institute, UCLA,Los Angeles, CA USA
  8. Department of Neurobiology, UCLA,Los Angeles, CA USA
  9. Department of Psychology, UCLA,Los Angeles, CA USA
  10. Integrative Center for Learning and Memory, UCLA,Los Angeles, CA USA
  11. Department of Cellular and Molecular Pharmacology, Howard Hughes Medical Institute, University of California,San Francisco, CA USA
  12. Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, David Geffen School of Medicine at UCLA,Los Angeles, CA USA
  13. Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA,Los Angeles, CA USA
Institutions: University of California, Los Angeles (United States); University of California, San Francisco (United States); Broad Center (United States); UCLA Jonsson Comprehensive Cancer Center
Journal: Nature communications, volume 17, issue 1, article 6386
Dates: received 18 July 2024; accepted 16 June 2026; published online 23 July 2026
Type: Research article · Language: English
License: CC BY
Identifiers: DOI 10.1038/s41467-026-74958-1 · PMID 42493511 · PMCID PMC13396360 · OpenAlex W7170136433
Open access: gold, a free copy (OpenAlex)
Status: data only
Categories: mouse (organism), autism (population), cellular / molecular (subfield)
Methods: Spectral & time-frequency, Statistics, Connectivity, Graphs, fMRI & imaging
Keywords: Autism spectrum disorders
MeSH: Autism Spectrum Disorder*, Inflammation*, Prenatal Exposure Delayed Effects*, Sirolimus*, Animals, Behavior, Animal, Brain, Disease Models, Animal, Female, Male, Mice, Mice, Inbred C57BL, Pregnancy, Signal Transduction, TOR Serine-Threonine Kinases (* major topic)
Topic: Autism Spectrum Disorder Research (Cognitive Neuroscience, Neuroscience), according to OpenAlex
Funding: Dr. Miriam and Sheldon G. Adelson Medical Research Foundation (Dr. Miriam & Sheldon G. Adelson Medical Research Foundation); U.S. Department of Health & Human Services | NIH | Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) (HD103557); Simons Foundation (SFI-AN-AR-Cross Species-00005172); Autism Speaks; National Institute of Mental Health (MH12205); Damon Runyon Cancer Research Foundation (Cancer Research Fund of the Damon Runyon-Walter Winchell Foundation) (DRG-2281-17); NINDS (UG3NS106945, NS09122, NS116383)
Citations: not cited yet (Europe PMC); 89 references in the paper

Abstract

Maternal inflammatory response (MIR) during early mouse gestation induces a cascade of physiological and behavioral changes associated with autism spectrum disorder (ASD). We have shown that mild MIR causes chronic systemic and brain inflammation, mTOR pathway activation, mild brain overgrowth with regionally specific volumetric changes, sensory processing dysregulation, and repetitive behavior abnormalities. Prior rapamycin studies in autism models focused on chronic treatments that alter or prevent physical brain changes. Here, we focus on acute rapamycin effects to uncover novel mTOR pathway-mediated mechanisms of dysfunction. Within 2 hours, rapamycin rescues neuronal hyperexcitability, seizure susceptibility, functional network connectivity, brain community structure, repetitive behaviors, and sensory over-responsivity in adult MIR offspring. These CNS-mediated effects coincide with altered expression of genes associated with ASD, ion channels, and epilepsy. Our findings demonstrate that mTOR dysregulation drives dysfunctional brain development in MIR offspring but the adult brain remains amenable to rapid functional normalization, rescuing core and comorbid ASD-associated brain and behavior phenotypes. Restoring excitatory/inhibitory imbalance and sensory functional network modularity may be important targets for therapeutically addressing multiple ASD phenotypes.

Reproduced under the paper's license (CC BY), from the paper cited above.

Code

The paper links to its data, not to its authors' code: see the Data section.

The paper's code and data availability statement is in the Data section.

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Data

Datasets cited

Data availability

The data that support the findings of this study are available as follows. Single-nucleus RNA sequencing data have been deposited in the NCBI Gene Expression Omnibus (GEO) under these accession codes [superseries #GSE328222 with subseries GSE328221 (single cell) and subseries GSE328220 (bulk)] and are publicly available as of the date of publication. Raw and preprocessed resting-state functional MRI and structural MRI data have been deposited in [Zenodo.org] under [10.5281/zenodo.19491368]. Univariate blood cytokine, western blot, brain wet weight, behavioral analysis, and slice electrophysiology data in this study have been deposited in [FigShare.com] under [10.6084/m9.figshare.31966476]. Source data underlying all figures and Supplementary Figs. are provided with this paper. Any additional information required to reanalyze the data reported in this paper is available from the corresponding author upon request. Source data are provided with this paper.

Reproduced under the paper's license (CC BY), from the paper cited above.

Versions

The history of this record: each version stored by the harvester or made by a correction of its authors or of the maintainers of its code, and what changed in its facts. The texts of the paper (its abstract, its availability statements) are not part of it; versions that changed only those are not listed.

Version 1, 27 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 14 authors, 1 keyword, 15 MeSH terms, 7 funders, 87 references.

Cite

This paper

Le Belle, J., Condro, M. C., Cepeda, C., Oikonomou, K., Tessema, K., Dudley, L., Schoenfield, J., Kawaguchi, R., Geschwind, D., Silva, A., Zhang, Z., Shokat, K., Harris, N., & Kornblum, H. (2026). Acute rapamycin treatment reveals distinct mechanisms of dysfunction in a maternal inflammation mouse model. Nature communications, 17(1), 6386. https://doi.org/10.1038/s41467-026-74958-1

BibTeX

@article{lebelle2026acute,
author = {Le Belle, JE and Condro, M. C. and Cepeda, C. and Oikonomou, KD and Tessema, K. and Dudley, L. and Schoenfield, J. and Kawaguchi, R. and Geschwind, D. and Silva, AJ and Zhang, Z. and Shokat, K. and Harris, NG and Kornblum, HI},
title = {{Acute rapamycin treatment reveals distinct mechanisms of dysfunction in a maternal inflammation mouse model}},
journal = {Nature communications},
year = {2026},
month = jul,
volume = {17},
number = {1},
pages = {6386},
publisher = {Nature Publishing Group},
issn = {2041-1723},
doi = {10.1038/s41467-026-74958-1},
url = {https://doi.org/10.1038/s41467-026-74958-1},
pmid = {42493511},
pmcid = {PMC13396360}
}

RIS

TY - JOUR
AU - Le Belle, JE
AU - Condro, M. C.
AU - Cepeda, C.
AU - Oikonomou, KD
AU - Tessema, K.
AU - Dudley, L.
AU - Schoenfield, J.
AU - Kawaguchi, R.
AU - Geschwind, D.
AU - Silva, AJ
AU - Zhang, Z.
AU - Shokat, K.
AU - Harris, NG
AU - Kornblum, HI
TI - Acute rapamycin treatment reveals distinct mechanisms of dysfunction in a maternal inflammation mouse model
T2 - Nature communications
J2 - Nat Commun
PY - 2026
DA - 2026/07/23
VL - 17
IS - 1
SP - 6386
SN - 2041-1723
PB - Nature Publishing Group
DO - 10.1038/s41467-026-74958-1
UR - https://doi.org/10.1038/s41467-026-74958-1
LA - en
ER -

CSL-JSON

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