Fractone-associated N-sulfated heparan sulfate shows reduced quantity in BTBR T+tf/J mice: A strong model of autism

Pacific Biosciences Research Center, University of Hawaii, 1993 East-West Road, Honolulu, HI 96822, USA.
Behavioural brain research (Impact Factor: 3.39). 11/2011; 228(2):247-53. DOI: 10.1016/j.bbr.2011.11.004
Source: PubMed

ABSTRACT BTBR T+tf/J (BTBR) mice show abnormal social, communicatory, and repetitive/stereotyped behaviors paralleling many of the symptoms of autism spectrum disorders. BTBR also show agenesis of the corpus callosum (CC) suggesting major perturbations of growth or guidance factors in the dorsal forebrain [1]. Heparan sulfate (HS) is a polysaccaride found in the brain and other animal tissues. It binds to a wide variety of ligands and through these ligands modulates a number of biological processes, including cell proliferation and differentiation, migration and guidance. It is aggregated on fractal-like structures (fractones) in the subventricular zone (SVZ), that may be visualized by laminin immunoreactivity (LAM-ir), as well as by HS immunoreactivity (HS-ir). We report that the lateral ventricles of BTBR mice were drastically reduced in area compared to C57BL/6J (B6) mice while the BTBR SVZ was significantly shorter than that of B6. In addition to much smaller fractones for BTBR, both HS and LAM-ir associated with fractones were significantly reduced in BTBR, and their anterior-posterior distributions were also altered. Finally, the ratio of HS to LAM in individual fractones was significantly higher in BTBR than in B6 mice. These data, in agreement with other findings linking HS to callosal development, suggest that variations in the quantity and distribution of HS in the SVZ of the lateral ventricles may be important modulators of the brain structural abnormalities of BTBR mice, and, potentially, contribute to the behavioral pathologies of these animals.

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Available from: Brandon L Pearson, Aug 19, 2015
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    • "Abnormal sulfation capacity [31] [38] [39] and decreased processing of paracetamol through sulfate conjugation has been consistently reported in low functioning autistic children [26]. Our lab has recently reported additional evidence for impaired sulfation for the BTBR mouse, with decreased N-sulfated heparan sulfate within the subventricular zone of the lateral ventricles [10] [40]. As this area is one of two neurogenic zones in adult mammals, and also very active in development, while heparan sulfate modulates the activity of an array of growth and guidance factors [41], this finding, compatible with the results of the present study, may provide additional possibilities with regard to mechanisms involved in autism. "
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    ABSTRACT: Clinical studies have shown that children diagnosed with autism show abnormal sulfate chemistry, which is critical for cellular and metabolic processes. To determine if the inbred BTBR T+tf/J mouse shows autism-relevant aberrations in sulfate chemistry, the present study examined plasma sulfate concentrations in BTBR T+tf/J, inbred C57BL/6J, and outbred CD-1 mice. Results showed that the BTBR T+tf/J mouse exhibits significantly lower plasma sulfate concentrations in comparison to both C57BL/6J and CD-1 mice. These results suggest that the BTBR mouse shows autism-relevant abnormalities in sulfate chemistry and may serve additional utility in examining the role of sulfate and sulfate-dependent systems in relation to autism-relevant behavioral aberrations.
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