Endothelial SLC38A2 controls brain D-serine homeostasis and synapse development.

Overview

Authors: Akshay K Tiwari¹, Ankita Lahkar¹, Clara Sajrawi¹, Yara Hussein², Adam Majcher³, Stephane Bonelli³, Bella Agranovich⁴, Ifat Abramovich⁴, Shani Stern², Farrukh A Chaudhry⁵, Thorsten Hornemann³, Inna Radzishevsky¹, Herman Wolosker^1,4

ORCID iDs: Stephane Bonelli, Herman Wolosker

Technion-Israel Institute of Technology, Ruth and Bruce Rappaport Faculty of Medicine, Department of Biochemistry, Haifa 3525433, Israel
Sagol Department of Neurobiology, Faculty of Natural Sciences, University of Haifa, Haifa 3103301, Israel
Institute of Clinical Chemistry, University of Zurich and University Hospital Zurich, 8091 Zurich, Switzerland
Technion-Israel Institute of Technology, Ruth and Bruce Rappaport Faculty of Medicine, Laura and Isaac Perlmutter Metabolomics Center, Haifa 3525433, Israel
The Institute of Basic Medical Sciences, University of Oslo, Blindern, 0317 Oslo, Norway

Institutions: Technion – Israel Institute of Technology (Israel); University of Haifa (Israel); University of Zurich (Switzerland); University Hospital Zurich (Switzerland); University of Oslo (Norway)

Journal: iScience, volume 29, issue 10, article 117487

Dates: received 8 May 2026; accepted 25 August 2026; published online 9 September 2026

Type: Research article · Language: English

License: CC BY

Identifiers: DOI 10.1016/j.isci.2026.117487 · PMID 42756628 · PMCID PMC13583979 · OpenAlex W7212031513

Open access: gold, a free copy (OpenAlex)

Status: code on request

Categories: cellular / molecular (subfield)

Methods: Statistics, Spectral & time-frequency

Keywords: serine, blood-brain barrier, D-serine, amino acid transport

Topic: Amino Acid Enzymes and Metabolism (Biochemistry, Biochemistry, Genetics and Molecular Biology), according to OpenAlex

Funding: Israel Science Foundation (ISF)

Citations: not cited yet (Europe PMC); 63 references in the paper

Research resources: RRID:AB_10847683, Goat polyclonal anti-CD31 RRID:AB_2161028, Rabbit polyclonal anti-PSAT1 RRID:AB_2172600, Mouse anti-GFAP RRID:AB_2294571, Mouse monoclonal anti-actin RRID:AB_2335127, Rabbit polyclonal NeuN RRID:AB_2651140, Mouse monoclonal anti PSD-95 RRID:AB_2698081, Rabbit polyclonal anti-Phgdh RRID:AB_2750870, Rabbit polyclonal anti SHMT2 RRID:AB_2798018, Rabbit polyclonal anti SHMT1 RRID:AB_2799957, Anti-gapdh RRID:AB_796208

Abstract

L-serine is a precursor for the synthesis of the neuromodulator D-serine, glycine, and lipids. Contrary to the prevailing view that brain L-serine is exclusively derived from de novo synthesis, we demonstrate that dietary L-serine is required to maintain brain L-serine levels and prevents the formation of neurotoxic 1-deoxysphingolipids. We identified SLC38A2 as an L-serine transporter at the blood-brain barrier (BBB) that mediates the influx of circulating L-serine to the brain. Endothelial-selective Slc38a2 conditional knockout (Slc38a2-cKO) decreased in vivo blood-to-brain L-serine influx and selectively lowered hippocampal L-serine and D-serine in mouse pups. Immunoelectron microscopy demonstrated that SLC38A2 is localized to both the luminal and abluminal endothelial membranes. Slc38a2-cKO pups exhibited ultrastructural defects at excitatory synapses, including reduced synaptic vesicle cluster size and decreased postsynaptic density area. SLC38A2 inhibition may be beneficial for limiting D-serine accumulation in conditions with pathologically elevated L- or D-serine levels, such as traumatic brain injury and epilepsy.

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

Code

The paper says that its authors' code is available on request: it was not published with the paper, so there is nothing to verify.

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

Tracing map

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Data

Datasets cited

geo:GSE330116, at NCBI GEO; found in “Data and code availability”

Data and code availability

The RNA-seq data generated in this study are available from GEO, accession number GSE330116 (https://ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE330116). Metabolomics spectra are publicly available in the massIVE database: https://massive.ucsd.edu/ (dataset MSV000101871). Sphingolipidomics spectra are available in the massIVE database (dataset MSV000101922).

This study did not generate new code.

Any additional information required to reanalyze the data reported in this paper is available from the lead contact upon request.

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 3, 28 September 2026

Authors: added Stephane Bonelli (0009-0009-4807-0212); Herman Wolosker (0000-0001-5508-9194); removed Stephane Bonelli; Herman Wolosker
Funding: added Israel Science Foundation

Version 1, 27 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 13 authors, 4 keywords, 63 references, 11 RRIDs.

Cite

This paper

Tiwari, A. K., Lahkar, A., Sajrawi, C., Hussein, Y., Majcher, A., Bonelli, S., Agranovich, B., Abramovich, I., Stern, S., Chaudhry, F. A., Hornemann, T., Radzishevsky, I., & Wolosker, H. (2026). Endothelial SLC38A2 controls brain D-serine homeostasis and synapse development. iScience, 29(10), 117487. https://doi.org/10.1016/j.isci.2026.117487

BibTeX

@article{tiwari2026endothelial, author = {Tiwari, Akshay K and Lahkar, Ankita and Sajrawi, Clara and Hussein, Yara and Majcher, Adam and Bonelli, Stephane and Agranovich, Bella and Abramovich, Ifat and Stern, Shani and Chaudhry, Farrukh A and Hornemann, Thorsten and Radzishevsky, Inna and Wolosker, Herman}, title = {{Endothelial SLC38A2 controls brain D-serine homeostasis and synapse development}}, journal = {iScience}, year = {2026}, month = sep, volume = {29}, number = {10}, pages = {117487}, publisher = {Elsevier}, issn = {2589-0042}, doi = {10.1016/j.isci.2026.117487}, url = {https://doi.org/10.1016/j.isci.2026.117487}, pmid = {42756628}, pmcid = {PMC13583979} }

RIS

TY - JOUR AU - Tiwari, Akshay K AU - Lahkar, Ankita AU - Sajrawi, Clara AU - Hussein, Yara AU - Majcher, Adam AU - Bonelli, Stephane AU - Agranovich, Bella AU - Abramovich, Ifat AU - Stern, Shani AU - Chaudhry, Farrukh A AU - Hornemann, Thorsten AU - Radzishevsky, Inna AU - Wolosker, Herman TI - Endothelial SLC38A2 controls brain D-serine homeostasis and synapse development T2 - iScience J2 - iScience PY - 2026 DA - 2026/09/09 VL - 29 IS - 10 SP - 117487 SN - 2589-0042 PB - Elsevier DO - 10.1016/j.isci.2026.117487 UR - https://doi.org/10.1016/j.isci.2026.117487 LA - en ER -

CSL-JSON

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