Comprehensive behavioral phenotyping of male Sulf1-deficient mice reveals reduced locomotor activity, altered forelimb gait, and reduced prepulse inhibition.
13 affiliations
- 1Department of Molecular Neurobiology, Institute of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, 305-8575, Ibaraki, Japan.
- 2Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Ibaraki, 305-8575, Japan.
- 3Division of Systems Medical Science, Center for Medical Science, Fujita Health University, Toyoake, Aichi, 470-1192, Japan.
- 4Genetic Engineering and Functional Genomics Group, Horizontal Medical Research Organization (HMRO), Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto, 606-8501, Japan.
- 5Department of Molecular Genetics, Institute of Basic Medical Sciences, University of Tsukuba, Ibaraki, 305-8575, Japan.
- 6Shizuoka Graduate University of Public Health, Shizuoka, Shizuoka, 420-0881, Japan.
- 7CREST, Japan Science and Technology Agency, Kawaguchi, Saitama, 332-0012, Japan.
- 8Addictive Substance Project, Tokyo Metropolitan Institute of Medical Science, Setagaya-ku, Tokyo, 156-8506, Japan.
- 9Department of Neuropsychopharmacology, National Institute of Mental Health, National Center of Neurology and Psychiatry, Kodaira, Tokyo, 187-8553, Japan.
- 10Division of Systems Medical Science, Center for Medical Science, Fujita Health University, Toyoake, Aichi, 470-1192, Japan. [email protected].
- 11Genetic Engineering and Functional Genomics Group, Horizontal Medical Research Organization (HMRO), Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto, 606-8501, Japan. [email protected].
- 12Department of Molecular Neurobiology, Institute of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, 305-8575, Ibaraki, Japan. [email protected].
- 13Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Ibaraki, 305-8575, Japan. [email protected].
Abstract
Sulfatase 1 (Sulf1) is an extracellular sulfatase that regulates multiple signaling pathways by removing 6-O-sulfate from heparan sulfate. Although Sulf1 has established roles in development and cancer, its functions in the adult brain remain incompletely characterized. Recently we reported that Sulf1 is expressed in the nucleus accumbens, overlapping with dopamine D1 and D2 receptors, and that Sulf1 knockout (KO) mice showed altered reward and aversion learning. However, given that Sulf1 is expressed in many other brain regions, including the prefrontal cortex, midline thalamic nuclei, etc., Sulf1 may have unknown brain functions. To explore the Sulf1 functions across a broad range of contexts, we here perform a comprehensive behavioral analysis of male Sulf1 KO mice, together with a re-analysis of the original data in which the false discovery rate (FDR) was controlled within defined groups of tests. Sulf1 KO mice traveled less than wild-type (WT) mice in the open field test, and this reduction was reproduced in an independent cohort. Gait analysis on a treadmill revealed a redistribution of the forelimb stance phase, with a larger proportion spent braking and a smaller proportion spent propelling, together with an increased absolute paw angle; these forelimb changes were reproduced in 2 independent cohorts and at 2 treadmill speeds. Distance traveled was also reduced in a three-chamber apparatus and, before drug injection, at nominal significance in the home cage. Sulf1 KO mice showed larger acoustic startle responses and reduced prepulse inhibition (PPI); the reduction in PPI was observed in all 5 drug-free or saline-treated sessions conducted in 2 independent cohorts and was also observed after haloperidol (0.3 or 1 mg/kg) and, at nominal significance, after clozapine (3 mg/kg) treatment. The locomotor, vertical, and stereotypic responses to methamphetamine were attenuated in Sulf1 KO mice, with nominally significant drug × genotype interactions. Increased baseline-subtracted contextual freezing provides a promising lead for further confirmation. Taken together, adult male Sulf1 KO mice exhibit alterations in locomotor output, forelimb gait, and sensorimotor gating, implicating that Sulf1 deficiency leads to a wide range of neurobehavioral abnormalities.
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BibTeX
@article{keinomasu2026comprehensive,
title = {{Comprehensive behavioral phenotyping of male Sulf1-deficient mice reveals reduced locomotor activity, altered forelimb gait, and reduced prepulse inhibition.}},
author = {Kazuko Keino-Masu and Markos Michail Chatzigiannis and Hirotaka Shoji and Nobuyuki Yamasaki and Takuya Okada and Yasue Horiuchi and Tadao Arinami and Yoko Hagino and Kazutaka Ikeda and Tsuyoshi Miyakawa and Masayuki Masu},
journal = {Molecular brain},
year = {2026},
month = oct,
doi = {10.1186/s13041-026-01353-8},
url = {https://europepmc.org/article/MED/42902403},
note = {CC BY},
}
RIS
TY - JOUR
TI - Comprehensive behavioral phenotyping of male Sulf1-deficient mice reveals reduced locomotor activity, altered forelimb gait, and reduced prepulse inhibition.
AU - Kazuko Keino-Masu
AU - Markos Michail Chatzigiannis
AU - Hirotaka Shoji
AU - Nobuyuki Yamasaki
AU - Takuya Okada
AU - Yasue Horiuchi
AU - Tadao Arinami
AU - Yoko Hagino
AU - Kazutaka Ikeda
AU - Tsuyoshi Miyakawa
AU - Masayuki Masu
PY - 2026
DA - 2026/10/17
JO - Molecular brain
DO - 10.1186/s13041-026-01353-8
UR - https://europepmc.org/article/MED/42902403
AB - Sulfatase 1 (Sulf1) is an extracellular sulfatase that regulates multiple signaling pathways by removing 6-O-sulfate from heparan sulfate. Although Sulf1 has established roles in development and cancer, its functions in the adult brain remain incompletely characterized. Recently we reported that Sulf1 is expressed in the nucleus accumbens, overlapping with dopamine D1 and D2 receptors, and that Sulf1 knockout (KO) mice showed altered reward and aversion learning. However, given that Sulf1 is expressed in many other brain regions, including the prefrontal cortex, midline thalamic nuclei, etc., Sulf1 may have unknown brain functions. To explore the Sulf1 functions across a broad range of contexts, we here perform a comprehensive behavioral analysis of male Sulf1 KO mice, together with a re-analysis of the original data in which the false discovery rate (FDR) was controlled within defined groups of tests. Sulf1 KO mice traveled less than wild-type (WT) mice in the open field test, and this reduction was reproduced in an independent cohort. Gait analysis on a treadmill revealed a redistribution of the forelimb stance phase, with a larger proportion spent braking and a smaller proportion spent propelling, together with an increased absolute paw angle; these forelimb changes were reproduced in 2 independent cohorts and at 2 treadmill speeds. Distance traveled was also reduced in a three-chamber apparatus and, before drug injection, at nominal significance in the home cage. Sulf1 KO mice showed larger acoustic startle responses and reduced prepulse inhibition (PPI); the reduction in PPI was observed in all 5 drug-free or saline-treated sessions conducted in 2 independent cohorts and was also observed after haloperidol (0.3 or 1 mg/kg) and, at nominal significance, after clozapine (3 mg/kg) treatment. The locomotor, vertical, and stereotypic responses to methamphetamine were attenuated in Sulf1 KO mice, with nominally significant drug × genotype interactions. Increased baseline-subtracted contextual freezing provides a promising lead for further confirmation. Taken together, adult male Sulf1 KO mice exhibit alterations in locomotor output, forelimb gait, and sensorimotor gating, implicating that Sulf1 deficiency leads to a wide range of neurobehavioral abnormalities.
SN - 1756-6606
ER -