heparitin-sulfate and Autistic-Disorder

Developmental disabilities are defined as disorders that result in the limitation of function due to impaired development of the nervous system; these disabilities can be present in the form of impairments in learning, language, behavior, or physical abilities. Examples of developmental disorders include attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), cerebral palsy (CP), hearing loss, blindness, intellectual disability, and learning disability. Of these disorders, ASD prevalence was 18.5 per 1000 children (1 in 54) aged 8 in 2016. Current literature suggests that deficient levels of heparan sulfate (HS), an acidic and linear glycosaminoglycan (GAG), is likely causative of ASD. The cascading effect of deficient HS levels can offer compelling evidence for the association of HS with ASD. Deficient levels of HS lead to defective Slit/Robo signaling, which affects axonal guidance and dendritic spine formation. Defective Slit/Robo signaling leads to increased Arp2/3 activity and dendritic spine density, which has been observed in the brains of persons with ASD. Therefore, interventions that target HS and its associated pathways may be viable treatment options for ASD.

Topics: Attention Deficit Disorder with Hyperactivity; Autism Spectrum Disorder; Autistic Disorder; Child; Heparitin Sulfate; Humans; Intellectual Disability

Neurexin synaptic organizing proteins are central to a genetic risk pathway in neuropsychiatric disorders. Neurexins also exemplify molecular diversity in the brain, with over a thousand alternatively spliced forms and further structural heterogeneity contributed by heparan sulfate glycan modification. Yet, interactions between these modes of post-transcriptional and post-translational modification have not been studied. We reveal that these regulatory modes converge on neurexin-1 splice site 5 (S5): the S5 insert increases the number of heparan sulfate chains. This is associated with reduced neurexin-1 protein level and reduced glutamatergic neurotransmitter release. Exclusion of neurexin-1 S5 in mice boosts neurotransmission without altering the AMPA/NMDA ratio and shifts communication and repetitive behavior away from phenotypes associated with autism spectrum disorders. Thus, neurexin-1 S5 acts as a synaptic rheostat to impact behavior through the intersection of RNA processing and glycobiology. These findings position NRXN1 S5 as a potential therapeutic target to restore function in neuropsychiatric disorders.

Topics: Alternative Splicing; Animals; Autistic Disorder; Brain; Heparitin Sulfate; Mice; Neural Cell Adhesion Molecules; Synapses; Synaptic Transmission

Abnormal cellular growth and organization have been characterized in postmortem tissue from brains of autistic individuals, suggestive of pathology in a critical neurogenic niche, the subventricular zone (SVZ) of the brain lateral ventricles (LV). We examined cellular organization, cell proliferation, and constituents of the extracellular matrix such as N-sulfated heparan sulfate (HS) and laminin (LAM) in postmortem brain tissue from the LV-SVZ of young to elderly individuals with autism (n=4) and age-matched typically developing (TD) individuals (n=4) using immunofluorescence techniques. Strong and systematic reductions in HS immunofluorescence were observed in the LV-SVZ of the TD individuals with increasing age. For young through mature, but not elderly, autistic pair members, HS was reduced compared to their matched TDs. Cellular proliferation (Ki67+) was higher in the autistic individual of the youngest age-matched pair. These preliminary data suggesting that HS may be reduced in young to mature autistic individuals are in agreement with previous findings from the BTBR T+tf/J mouse, an animal model of autism; from mice with genetic modifications reducing HS; and with genetic variants in HS-related genes in autism. They suggest that aberrant extracellular matrix glycosaminoglycan function localized to the subventricular zone of the lateral ventricles may be a biomarker for autism, and potentially involved in the etiology of the disorder.

Topics: Adult; Autistic Disorder; Cell Proliferation; Child, Preschool; Extracellular Matrix; Heparitin Sulfate; Humans; Laminin; Lateral Ventricles; Male; Middle Aged; Neurogenesis; Tissue Banks; Young Adult

BTBR T+tf/J (BTBR) mice have emerged as strong candidates to serve as models of a range of autism-relevant behaviors, showing deficiencies in social behaviors; reduced or unusual ultrasonic vocalizations in conspecific situations; and enhanced, repetitive self-grooming. Recent studies have described their behaviors in a seminatural visible burrow system (VBS); a Social Proximity Test in which avoidance of a conspecific is impossible; and in an object approach and investigation test evaluating attention to specific objects and potential stereotypies in the order of approaching/investigating objects. VBS results confirmed strong BTBR avoidance of conspecifics and in the Social Proximity Test, BTBR showed dramatic differences in several close-in behaviors, including specific avoidance of a nose-to-nose contact that may potentially be related to gaze-avoidance. Diazepam normalized social avoidance by BTBRs in a Three-Chamber Test, and some additional behaviors - but not nose to nose avoidance - in the Social Proximity Test. BTBR also showed higher levels of preference for particular objects, and higher levels of sequences investigating 3- or 4-objects in the same order. Heparan sulfate (HS) associated with fractal structures in the subventricular zone of the lateral ventricles was severely reduced in BTBR. HS may modulate the functions of a range of growth and guidance factors during development, and HS abnormalities are associated with relevant brain (callosal agenesis) and behavioral (reductions in sociality) changes; suggesting the value of examination of the dynamics of the HS system in the context of autism.

Topics: Animals; Autistic Disorder; Disease Models, Animal; Exploratory Behavior; Grooming; Heparitin Sulfate; Humans; Male; Mice; Mice, Inbred Strains; Social Behavior

Multiple studies converge to implicate alterations of the hippocampus and amygdala in the pathology of autism. We have previously reported anatomical alterations of the meninges, vasculature and fractones, the specialized extracellular matrix (ECM) of the subventricular zone, in the forebrain of adult BTBR T+ tf/J mice, animal model for autism. Here, we used bisbenzidine cell nucleus staining and dual immunofluorescence histochemistry for laminin and N-sulfated heparan sulfate proteoglycans (NS-HSPG) to examine a series of brain sections containing the amygdala and hippocampus in the adult BTBR T+ tf/j mouse. We observed an excessive separation of the two hippocampi, a modified trajectory of the meninges leading to a shrunken choroid plexus in the lateral ventricle, a shorter granular layer of the dentate gyrus, and a reduced size of the amygdala nuclei. The lateral ventricle near the amygdala, and the third ventricle were shrunken. The number and size of fractones, and their immunoreactivity for NS-HSPG, were reduced throughout the third and lateral ventricles walls. Enlarged blood vessels were found at the endopiriform cortex/amygdala interface. These results show anatomical alterations of the hippocampal/amygdala that are associated with defects of the choroid plexus/ventricular system and the ECM in the BTBR T+ TF/J mouse. Similar alterations of the hippocampus/amygdala axis in humans with autism to these observed in BTBR T+ tf/J mice make this animal model highly valuable for the study of autism. Moreover, the meningo/vascular and ECM alterations in BTBR T+ Tf/J mice suggest a possible role of the brain connective tissue in autism.

Topics: Amygdala; Animals; Autistic Disorder; Cerebral Ventricles; Disease Models, Animal; Extracellular Matrix; Female; Fluorescent Antibody Technique; Heparitin Sulfate; Hippocampus; Male; Mice; Mice, Neurologic Mutants

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.

Topics: Analysis of Variance; Animals; Autistic Disorder; Brain; Corpus Callosum; Disease Models, Animal; Heparitin Sulfate; Lamins; Lateral Ventricles; Male; Mice; Mice, Inbred C57BL; Mice, Neurologic Mutants; Phenotype

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.

Topics: Amygdala; Animals; Autistic Disorder; Communication; Heparitin Sulfate; Immunohistochemistry; Mice; Mice, Inbred C57BL; Mice, Knockout; N-Acetylglucosaminyltransferases; Nervous System; Neurons; Organ Specificity; Phenotype; Proto-Oncogene Proteins c-fos; Social Behavior; Stereotypic Movement Disorder; Synaptic Transmission

Topics: Animals; Autistic Disorder; Disease Models, Animal; Heparitin Sulfate; Mice; Mice, Inbred Strains