Journal article
A chromosome region linked to neurodevelopmental disorders influences locomotor behavior through sex-specific neural circuits
Nature communications, Vol.17(1), 107
01/03/2026
DOI: 10.1038/s41467-025-68047-y
PMCID: PMC12774972
PMID: 41484117
Abstract
Biological sex shapes the manifestation and progression of neurodevelopmental disorders (NDDs), however, the underlying mechanisms remains unclear. Hemideletion of the 16p11.2 region (16p11.2 del/+) is associated with NDDs, and 16p11.2 del/+ mice exhibit sex-specific, striatum-related phenotypes relevant to NDDs. In this study, using snRNA-seq, we identify cell type- and sex-specific transcriptomic changes in D1- and D2-spiny projection neurons (SPNs), with greater impact in males. Fiber photometry recordings reveal reduced neuronal activity in the dorsal striatum of 16p11.2 del/+ males, but not females, with D2-SPNs identified as the primary contributors to this reduction. Behaviorally, we utilize conditional genetic approaches and find that selective hemideletion in D2-SPNs, but not D1-SPNs, induces male-specific hyperactivity, whereas cortical hemideletion increases hyperactivity in both sexes. Thus, a locus linked to NDDs acts in distinct striatal circuits, selectively impacting behavior in a sex- and cell type-specific manner.
This study demonstrates that 16p11.2 hemideletion, a genetic deletion linked to neurodevelopmental disorders, affects male and female mice differently, altering specific striatal neuronal circuits and driving sex-specific behavioral changes.
Details
- Title: Subtitle
- A chromosome region linked to neurodevelopmental disorders influences locomotor behavior through sex-specific neural circuits
- Creators
- Jaekyoon Kim - University of IowaYann Vanrobaeys - University of IowaRemya Rajan - University of Iowa, Roy J. Carver Department of Biomedical EngineeringM. Felicia Davatolhagh - University of California, Los AngelesBenjamin Kelvington - University of IowaSnehajyoti Chatterjee - University of IowaSarah L. Ferri - University of IowaChristopher Angelakos - Stanford UniversityAlea A. Mills - Cold Spring Harbor LaboratoryMarc V. Fuccillo - University of PennsylvaniaKim T. Blackwell - University of IowaThomas Nickl-Jockschat - German Centre for Cardiovascular ResearchTed Abel - University of Iowa
- Resource Type
- Journal article
- Publication Details
- Nature communications, Vol.17(1), 107
- DOI
- 10.1038/s41467-025-68047-y
- PMID
- 41484117
- PMCID
- PMC12774972
- NLM abbreviation
- Nat Commun
- ISSN
- 2041-1723
- eISSN
- 2041-1723
- Publisher
- Nature Publishing Group UK
- Grant note
- HAWK-IDDRC P50 HD103556 / U.S. Department of Health & Human Services | NIH | Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) (https://doi.org/10.13039/100009633) R01 MH 087463 / U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (NIMH) (https://doi.org/10.13039/100000025) SFARI 345034 / Simons Foundation (https://doi.org/10.13039/100000893)
- Language
- English
- Date published
- 01/03/2026
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Molecular Physiology and Biophysics; Psychiatry; Stead Family Department of Pediatrics; Psychological and Brain Sciences; Iowa Neuroscience Institute; Developmental and Behavioral Pediatrics; Neuroscience and Pharmacology; Biochemistry and Molecular Biology
- Record Identifier
- 9985114170902771
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