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APOE4 and doxorubicin impair inhibitory interneuron function and homeostatic regulation in the entorhinal cortex.

Overview

Authors: Nancy Luo1,2, Harshul Pandit2, Shreya Kalra2, Erin Tran2, Jeanne Mandelblatt3, Stefano Vicini4, G William Rebeck1,2
ORCID iDs: Nancy Luo, Harshul Pandit, G William Rebeck
  1. Interdisciplinary Program in Neuroscience, Georgetown University, Washington D.C., United States of America
  2. Department of Neuroscience, Georgetown University, Washington D.C., District of Columbia, United States of America
  3. Department of Oncology, Georgetown Lombardi Institute for Cancer and Aging Research (I-CARE), Lombardi Comprehensive Cancer Center, Georgetown University, Washington D.C., United States of America
  4. Department of Pharmacology and Physiology, Georgetown University, Washington D.C., United States of America
Institutions: Georgetown University (United States); Georgetown Lombardi Comprehensive Cancer Center (United States)
Journal: PloS one, volume 21, issue 3, article e0343276
Dates: received 21 November 2025; accepted 3 February 2026; published online 26 March 2026
Type: Research article · Language: English
License: CC BY
Identifiers: DOI 10.1371/journal.pone.0343276 · PMID 41886471 · PMCID PMC13020844 · OpenAlex W7140642334
Open access: gold, a free copy (OpenAlex)
Status: data only (how the code is found and verified)
Categories: human (organism), mouse (organism), Alzheimer's / dementia (population), systems (subfield)
Methods: Statistics, Preprocessing, fMRI & imaging, Single-unit activity, calcium imaging
MeSH: Apolipoprotein E4*, Doxorubicin*, Entorhinal Cortex*, Homeostasis*, Interneurons*, Animals, Humans, Male, Mice, Mice, Transgenic, Parvalbumins, Pyramidal Cells (* major topic)
Topic: Cancer-related cognitive impairment studies (Oncology, Medicine), according to OpenAlex
Funding: NIA NIH HHS (T32 AG071745, F30 AG082448); NCI NIH HHS (R35 CA283926)
Citations: not cited yet (Europe PMC); 73 references in the paper

Abstract

APOE4 is a risk factor for several disease states associated with cognitive impairment, including Alzheimer’s disease and cancer-chemotherapy induced cognitive impairment. Using mouse knock-in models of human APOE alleles, we examined the effects of APOE genotype and chemotherapy on the ex vivo electrophysiological characteristics of excitatory and inhibitory neurons in the entorhinal cortex (EC). We found that APOE4 is associated with a significantly higher excitatory/inhibitory ratio (0.33 ± 0.04) in the layer 2/3 pyramidal cells of the entorhinal cortex compared to APOE3 (0.19 ± 0.04). We crossed APOE mice to mice with parvalbumin (PV) interneurons tagged with tdTomato, allowing us to measure effects specifically on this inhibitory cell type. For EC pyramidal neurons, the chemotherapeutic agent doxorubicin caused increases in the amplitudes of both spontaneous excitatory and inhibitory post-synaptic currents, with significant responses (***p < 0.001; **p < 0.01 respectively) in APOE3 brains. For EC PV neurons, APOE4 genotype was associated with significantly lower firing rates at injections of high currents (**p < 0.01), but rates were unaffected by doxorubicin. Doxorubicin doubled the percentage of PV cells that showed inactivation block in APOE3 brains (25% to 52%) but had no effect on APOE4 brains (50% to 54%). This ex vivo study suggests that APOE4 impairs homeostatic synaptic transmission in pyramidal cells under control conditions and causes a lack of responsiveness to a stressor (doxorubicin treatment) in PV cells.

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

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Data

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Data Availability

The data underlying the results presented in the study are available through the Guidelines International network, https://doi.org/10.12751/g-node.qybv42.

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

Versions

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Version 1, 30 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 7 authors, 12 MeSH terms, 2 funders, 72 references.

Cite

This paper

Luo, N., Pandit, H., Kalra, S., Tran, E., Mandelblatt, J., Vicini, S., & Rebeck, G. W. (2026). APOE4 and doxorubicin impair inhibitory interneuron function and homeostatic regulation in the entorhinal cortex. PloS one, 21(3), e0343276. https://doi.org/10.1371/journal.pone.0343276

BibTeX

@article{luo2026apoe4,
author = {Luo, Nancy and Pandit, Harshul and Kalra, Shreya and Tran, Erin and Mandelblatt, Jeanne and Vicini, Stefano and Rebeck, G William},
title = {{APOE4 and doxorubicin impair inhibitory interneuron function and homeostatic regulation in the entorhinal cortex}},
journal = {PloS one},
year = {2026},
month = mar,
volume = {21},
number = {3},
pages = {e0343276},
publisher = {PLOS},
issn = {1932-6203},
doi = {10.1371/journal.pone.0343276},
url = {https://doi.org/10.1371/journal.pone.0343276},
pmid = {41886471},
pmcid = {PMC13020844}
}

RIS

TY - JOUR
AU - Luo, Nancy
AU - Pandit, Harshul
AU - Kalra, Shreya
AU - Tran, Erin
AU - Mandelblatt, Jeanne
AU - Vicini, Stefano
AU - Rebeck, G William
TI - APOE4 and doxorubicin impair inhibitory interneuron function and homeostatic regulation in the entorhinal cortex
T2 - PloS one
J2 - PLoS One
PY - 2026
DA - 2026/03/26
VL - 21
IS - 3
SP - e0343276
SN - 1932-6203
PB - PLOS
DO - 10.1371/journal.pone.0343276
UR - https://doi.org/10.1371/journal.pone.0343276
LA - en
ER -

CSL-JSON

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