A chromosome region linked to neurodevelopmental disorders influences locomotor behavior through sex-specific neural circuits

Kim, Jaekyoon, Vanrobaeys, Yann, Rajan, Remya, Davatolhagh, M Felicia, Kelvington, Benjamin, Chatterjee, Snehajyoti, Ferri, Sarah L, Angelakos, Christopher, Mills, Alea A, Fuccillo, Marc V, Blackwell, Kim T, Nickl-Jockschat, Thomas, Abel, Ted (January 2026) A chromosome region linked to neurodevelopmental disorders influences locomotor behavior through sex-specific neural circuits. Nature Communications, 17 (1). p. 107. ISSN 2041-1723

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URL: https://www.ncbi.nlm.nih.gov/pubmed/41484117

DOI: 10.1038/s41467-025-68047-y

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.

Item Type:	Paper
Subjects:	organism description > animal organism description > animal > developmental stage organism description > animal > mammal organism description > animal > mammal > rodent > mouse organism description > animal > developmental stage > neurodevelopment organism description > animal > mammal > rodent
CSHL Authors:	Mills, Alea A.
Communities:	CSHL labs > Mills lab
SWORD Depositor:	CSHL Elements
Depositing User:	CSHL Elements
Date:	3 January 2026
Date Deposited:	12 Jan 2026 14:02
Last Modified:	12 Jan 2026 14:02
PMCID:	PMC12774972
Related URLs:	Publisher
URI:	https://repository.cshl.edu/id/eprint/42065

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