biostudies-literatureKim JSimons FoundationU.S. Department of Health & Human Services | NIH | National Institute of Mental Health (NIMH)NICHD NIH HHSNIDA NIH HHSNIMH NIH HHSU.S. Department of Health & Human Services | NIH | Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)U.S. Department of Health & Human Services | NIH | National Institute of Mental HealthNIGMS NIH HHSU.S. Department of Health & Human Services | NIH | Eunice Kennedy Shriver National Institute of Child Health and Human Development107https://www.ebi.ac.uk/biostudies/studies/S-EPMC12774972biostudies-literatureUnknown17(1)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-SNature communicationsA chromosome region linked to neurodevelopmental disorders influences locomotor behavior through sex-specific neural circuits.PMC12774972SFARI 345034P50 HD103556F31 MH134542HAWK-IDDRC P50 HD103556R01 MH115030R01 DA056113T32 GM067795R01 MH087463R01 MH 087463Nickl-Jockschat TDavatolhagh MFAbel TVanrobaeys YFerri SLKim JAngelakos CBlackwell KTRajan RMills AAFuccillo MVKelvington BChatterjee SfalseA chromosome region linked to neurodevelopmental disorders influences locomotor behavior through sex-specific neural circuits.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-S2026-01-01T00:00:00Z2026 Jan2026-07-15T13:22:06.488Z2026-07-05T03:08:18.472ZS-EPMC127749724148411710.1038/s41467-025-68047-y