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: 3.03). 11/2011; 228(2):247-53. DOI: 10.1016/j.bbr.2011.11.004
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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, Sep 26, 2015
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    • "A view that behavior stems directly from the situationally responsive activities of brain systems, reflecting their development and current functioning, suggests that there may be brain system or other biological differences between BTBR mice and strains such as C57BL/6 mice, the latter representing a centrist position with respect to sociality (reviewed in Meyza et al., 2012). The discovery that levels of the glycosaminoglycan, heparan sulfate (HS) are strikingly reduced in the lateral ventricle subventricular zone of the BTBR mouse (Meyza et al., 2012) provided a candidate for this mutual aberration (Fig. 3). The heparan sulfate proteoglycan consists of a core protein to which HS chains consisting of variably sulfated repeating disaccharide units are attached. "
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    ABSTRACT: The history of science has frequently included a problem-based impetus toward research that can be translated expeditiously into solutions. A current problem is that psychopathologies, typically chronic, contribute hugely to the economic and social burden of medical care, especially in the United States. For behavioral neuroscientists a psychopathology-aimed translational research emphasis particularly involves animal models to facilitate the experimental and invasive work necessary to an understanding of the biology of normal and aberrant behavior. When the etiology of a particular psychopathology is unknown, and there are no specific biomarkers, behavioral parallels between the focal disorder and its putative models become crucial elements in assessing model validity. Evaluation of these parallels is frequently neglected, reflecting in part the lack of a systematic conceptualization of the organization of behavior and how this may be conserved across species. Recent work specifically attempting to bridge this gap suggests that analysis of behaviors that are functional - adaptive in crucial situations such as danger or social contexts - can facilitate an understanding of the parallels between behaviors of human and nonhuman species, including the dysfunctional behaviors of psycho-pathologies. As research with animal models comes to provide a more systematic analysis of particular behaviors and their adaptive functions, cross-talk between model and focal psychopathology may be advantageous to understanding both.
    Neuroscience & Biobehavioral Reviews 06/2013; 37(8). DOI:10.1016/j.neubiorev.2013.06.008 · 8.80 Impact Factor
    • "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.
    Physiology & Behavior 04/2012; 107(5). DOI:10.1016/j.physbeh.2012.04.010 · 2.98 Impact Factor
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    ABSTRACT: Heparan sulfate regulates diverse cell-surface signaling events, and its roles in the development of the nervous system recently have been increasingly uncovered by studies using genetic models carrying mutations of genes encoding enzymes for its synthesis. On the other hand, the role of heparan sulfate in the physiological function of the adult brain has been poorly characterized, despite several pieces of evidence suggesting its role in the regulation of synaptic function. To address this issue, we eliminated heparan sulfate from postnatal neurons by conditionally inactivating Ext1, the gene encoding an enzyme essential for heparan sulfate synthesis. Resultant conditional mutant mice show no detectable morphological defects in the cytoarchitecture of the brain. Remarkably, these mutant mice recapitulate almost the full range of autistic symptoms, including impairments in social interaction, expression of stereotyped, repetitive behavior, and impairments in ultrasonic vocalization, as well as some associated features. Mapping of neuronal activation by c-Fos immunohistochemistry demonstrates that neuronal activation in response to social stimulation is attenuated in the amygdala in these mice. Electrophysiology in amygdala pyramidal neurons shows an attenuation of excitatory synaptic transmission, presumably because of the reduction in the level of synaptically localized AMPA-type glutamate receptors. Our results demonstrate that heparan sulfate is critical for normal functioning of glutamatergic synapses and that its deficiency mediates socio-communicative deficits and stereotypies characteristic for autism.
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