Calretinin and Parvalbumin Trapping of TDP43 and XRCC1 Instructs Neocortical Interneuron Death in Neonatal Hypoxic-Ischemic Encephalopathy.

Overview

1. Department of Pathology, Division of Neuropathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, (D.F.); (A.G.); (N.A.); (D.P.)
2. Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
3. Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
4. The Pathobiology Graduate Training Program, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
5. Department of Neurology, The Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA

Abstract

We examined neocortical pathology and interneuron degeneration in neonatal hypoxia-ischemic encephalopathy (HIE). Piglets in two age groups (2–3 or 7–10 days old, n = 4–12/group) underwent global cerebral hypoxia–ischemia (HI) or sham treatment. Piglets (2–3 days old) had epidural electrodes for continuous electroencephalography (cEEG) and were treated with hypothermia (HT) or remained at normothermia (NT). Older piglets, all NT, had scalp EEG. Piglets at both ages had seizures and survived for 1–7 days. Cortical damage was assessed by hematoxylin & eosin staining and immunohistochemistry; calretinin (CR), parvalbumin (PV), and vasoactive intestinal peptide (VIP) interneurons (INs) were counted. Cell injury was assessed by DNA fragmentation and protein nitration. TAR DNA binding protein-43 (TDP43) and the DNA repair scaffold protein X-ray repair cross complementing-1 (XRCC1) were examined for degeneration mechanisms. Cortical layers 3 and 4 showed high vulnerability; damage emerged as isolated cells, focal and laminar, and distributed as panlaminar throughout different cortical regions that correlated with seizure burden. HT protected strongly against cortical damage. CR- and PV-INs were severely depleted in HI-NT piglets compared to sham. VIP INs appeared invulnerable. HT partially rescued the loss of INs. CR and PV formed nuclear and cytoplasmic inclusions that colocalized with TDP43 and XRCC1; co-immunoprecipitation identified interactions among these proteins, and tyrosine nitration of CR. CR and PV INs accumulated DNA single- and double-strand breaks and appeared as attritional apoptosis variants with proteinopathy. This cell death is identified as aggreosis. IN loss correlated with seizure presence. Postmortem human neonatal HIE cases had a similar loss of CR and PV INs and nuclear depletion of TDP43 in the neocortex. Thus, neonatal HIE causes the loss of neocortical inhibitory IN subtypes with vulnerabilities instructed by their intrinsic calcium-binding protein signature and by mechanisms consistent with toxic sequestration and the nuclear depletion of XRCC1 and TDP43 underlying DNA damage accumulation. Early inhibitory IN deletion could drive seizure evolution in HIE; TDP43 and XRCC1 could be therapeutic targets for neonatal HIE.

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.

Tracing map

A tracing map links a paper to the code its authors published: this paper has none, so it has no map.

Data

Datasets cited

• uniprot.org/uniprotkb/p20472, at UniProt; found in the text, “4.5. CR Is Nitrated in HI Piglet Cerebral Cortex”
• uniprot.org/uniprotkb/p22676, at UniProt; found in the text, “4.5. CR Is Nitrated in HI Piglet Cerebral Cortex”

Data Availability Statement

The original contributions presented in this study are included in the article/Supplementary Materials. Further inquiries can be directed to the Lee J. Martin.

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, 29 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 10 authors, 7 keywords, 11 MeSH terms, 1 funder, 102 references.

Cite

This paper

Martin, L. J., Ichord, R. N., O’Brien, C. E., Yohannan, S., Fernandez, D., Garrido, A., Amauri, N., Park, D., Benderoth, J., & Lee, J. K. (2026). Calretinin and Parvalbumin Trapping of TDP43 and XRCC1 Instructs Neocortical Interneuron Death in Neonatal Hypoxic-Ischemic Encephalopathy. Biomolecules, 16(5), 621. https://doi.org/10.3390/biom16050621

Similar papers

The papers with a page that share the most with this one: the tools found in their code, their categories, datasets, cited references and authors, the rarest counting most.

[1] doi:10.1186/s13024-026-00944-2

TDP-43: [GU]-ardian of the transcriptome.

Journal: Molecular neurodegeneration

In common: other condition, 3 references

[2] doi:10.3390/neurosci7040079 [code]

Effect of Caffeine on Cell Death, Oxidative Stress, and Microglial Morphology in a Ferret Organotypic Brain Slice Model of Hypoxia-Ischemia.

Journal: NeuroSci

In common: other, 2 references

[3] doi:10.3389/fnsyn.2026.1843277 [code]

High-frequency, high-intensity electrical stimulation selectively activates human fast-spiking interneurons.

Journal: Frontiers in synaptic neuroscience

In common: epilepsy, 2 references

[4] doi:10.1162/imag.a.1279 [code]

Multimodal laminar characterization of visual areas along the cortical hierarchy.

Journal: Imaging neuroscience (Cambridge, Mass.)

In common: histology / microscopy, 2 references

[5] doi:10.1038/s41467-026-72334-7 [code]

RNA targeting therapy for a prenatally enriched potassium channel associated with severe childhood epilepsy and premature death.

Journal: Nature communications

In common: epilepsy, 1 reference

[6] doi:10.1038/s41467-026-71360-9 [code]

Perinatal brain developmental transition revealed by transcriptomic and proteomic analyses of Bama miniature pigs.

Journal: Nature communications

In common: other, 1 reference

[7] doi:10.1016/j.isci.2026.116776 [code]

Selective perturbation of mirror and non-mirror neurons in an in silico model of the action observation network.

Journal: iScience

In common: 2 references

[8] doi:10.1038/s42003-026-10418-2 [code]

Cortical PV and VIP interneurons similarly influence SST neuron output despite distinct unitary properties.

Journal: Communications biology

In common: 2 references

[9] doi:10.1038/s41592-026-03125-7

Simultaneous two- and three-photon multiplane imaging across cortical layers in freely moving mice.

Journal: Nature methods

In common: histology / microscopy, 1 reference

[10] doi:10.1038/s41598-026-54127-6

Canonical autophagy remains inactive in induced pluripotent stem cells and neuronal progenitor cells following DNA damage induced by BPDE or etoposide.

Journal: Scientific reports

In common: other condition, 1 reference

Contribute

The authors of this paper can claim it, correct its record and validate its tracing map, and the maintainers of its code (its owner, or a public member of its organization) correct what it says of their repository; anyone signed in can ask for its removal. Every request goes to OSCR's own machine, which answers it; your account page follows them.

Request its removal

To ask OSCR to remove this record, the copies of its authors' scripts or its tracing map, use the removal request page: signed in, you say who you are, what to remove and why, then review and confirm the request. Published rules decide every request (how).

Discussion: questions and error reports about this paper and its code, from signed-in readers and its authors. It opens with sign-in.

Reproductions: reports from readers who ran the authors' code: what they reproduced, with which environment, commit and data. It opens with sign-in.

Activity: what happens around this paper: new versions of its record, its map's validation, discussions and reproductions. It opens with sign-in.