Hippocampal small RNAs from patients with schizophrenia induce specific cognitive and neural phenotypes in mice.

Overview

1. Departament de Biomedicina, Facultat de Medicina, Institut de Neurociències, Universitat de Barcelona, Barcelona, Spain
2. Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
3. Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain
4. Production and Validation Centre of Advanced Therapies (Creatio), Faculty of Medicine and Health Science, University of Barcelona, Barcelona, Spain
5. Parc Sanitari Sant Joan de Déu, CIBERSAM, Barcelona, Spain

Abstract

Schizophrenia is a neuropsychiatric syndrome characterized by the presence of psychotic, negative and cognitive symptoms. Cognitive deficits can appear even before the onset of the first psychotic episode and their severity has been recently associated with altered levels of small RNAs (sRNAs), including microRNAs. Nevertheless, how the dysregulation of sRNAs can lead to cognitive impairments and their role in the onset and pathophysiology of the disorder are still unknown. In our research, we hypothesized that hippocampal sRNAs generated in patients with schizophrenia could contribute to the impairment of specific cognitive domains that are altered in the disease. Through deep sequencing, we identified novel dysregulated sRNAs (including microRNAs and tRNA-derived fragments) in the hippocampus of patients with schizophrenia. Furthermore, when injected in the hippocampus of wild-type mice, animals exhibited an impairment in spatial short-term memory accompanied by a reduction in spine density of CA1 pyramidal neurons. RNA-sequencing of the hippocampus of injected mice revealed changes in key pathways related to neurotransmission. Specifically, we found higher levels of the presynaptic marker for Parvalbumin interneurons synaptotagmin II (Syt2), mirroring observations made in the brain of schizophrenia patients. We also detected subtle morphological changes in mouse hippocampal microglia in response to sRNAs from affected individuals. Our results point out that sRNAs can contribute to cognitive symptoms in schizophrenia through synaptic alterations, highlighting these molecules as promising novel therapeutic targets for the disorder.

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Data

Datasets cited

• geo:GSE325449, at NCBI GEO; found in “Data availability”

Data availability

Sequencing data has been deposited in NCBI’s Gene Expression Omnibus and are accessible through GEO Series accession number (GSE325449 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE325449)). Rest of data and materials will be made available upon reasonable request.

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

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Version 2, 28 September 2026

• Funding: added European Commission: 100010434, 10.13039/501100011033, 13039/501100011033, 501100011033, CEX2021-001159-M, ID 100010434; Ministerio de Ciencia e Innovación: 13039/501100011033, ID100010434, CEX2021-001159-M, 10.13039, CEX2021-001159, 13039, 10.13039/501100011033/, 100010434, PID2021-122258OB-I00, 501100011033, PID2024-157024OB-I00, /AEI/10.13039/ 501100011033; Universitat de Barcelona: CEX2021-001159-M; Agencia Estatal de Investigación: AEI//10.13039/501100011033/, 501100011033, 10.13039/501100011033, 13039, 13039/501100011033, PID2023, 10.13039, 100010434, PID2021-122258OB-I00, PID2023-146279OB-I00, AEI/10.13039 / 501100011033/FEDER, PID2021, CEX2021-001159-M

Version 1, 28 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 10 authors, 2 keywords, 74 references.

Cite

This paper

Galán-Ganga, M., Guisado-Corcoll, A., Sancho-Balsells, A., Herrero-Lorenzo, M., Ballasch, I., Patterer, L., Alberch, J., Arranz, B., Giralt, A., & Martí, E. (2026). Hippocampal small RNAs from patients with schizophrenia induce specific cognitive and neural phenotypes in mice. Cell death discovery, 12(1), 315. https://doi.org/10.1038/s41420-026-03166-z

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