Comprehensive behavioral phenotyping of male Sulf1-deficient mice reveals reduced locomotor activity, altered forelimb gait, and reduced prepulse inhibition

Abstract

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.