Autism Spectrum Disorder

The early signs of ASD, uploaded by KennedyKrieger

Autism spectrum disorder (ASD) are a range of behavioural abnormalities comprising social interaction impairments, communication deficits, and restricted or repetitive interests.1 Diagnosistic criteria according to the current edition of the Diagnostic and Statistical Manual of Mental Disorders, DSM-V, emphasize symptoms presenting in early childhood. Prognosis is hindered by the lack of solid and complete understanding of the pathological causes or mechanisms of the disorders. Although genes are certainly involved in ASD etiology, it is becoming evident that there are also other significant contributing factors; such as epigenetic abnormalities, antibody and cytokine dysregulation, and neural or synaptic changes.

1.1 Genes and the Environment

1.1a Genetics

Autism spectrum disorder is usually associated with genetic neurodevelopmental disorders such as Fragile X1 and Rett Syndrome2, which both share behavioural symptoms with ASD.

Image Unavailable
Figure 1. Large copy-number variants found in ASD (blue),
developmental delay (red), and controls (green
Image Source: Girirajan et al, 2013

Copy number variants (CNVs) (Fig1) resulting from nonallelic homologous recombination is another approach to finding critical genes. Copy number variants have been proposed to contribute to autism, although the overlap with other developmental disorders obscures their exact role in the pathogenesis. In any case, most CNVs encode pre- and post-synaptic components (e.g.., neurexin, neuroligins, and cell adhesion molecules)3

Image Unavailable
Figure 2. The SNPs common to four subtypes of ASD.
Image Source: Hu et al., 2011

Due to advances in gene-sequencing techniques, the single gene approach has been replaced with genome wide association studies (GWAS). The delineation of the genetic ASD profile by these means has been a rather onerous process that is only recently starting to yield useful results (most likely due to the highly heterogeneous nature of the disorder). In any case, a monumental study discovered 18 novel single-nucleotide polymorphisms (SNPs), out of over 500,000 investigated SNPs(Fig2).4 The SNPs were associated with four subtypes of ASD (i.e., mild, moderate, intermediate, and language), and they were all located in nonexonic regions of DNA. Further investigation of these SNPs, among others, will help elucidate abnormal molecular pathways in ASD, and will potentially help develop gene therapy treatments.

1.1b Epigenetics

Image Unavailable
Figure 3. Immunohistochemical staining for RORA and Bcl2 in
the cerebellum of ASD subjects and controls. Arrows indicate Purkinje cells.
Image Source: Nguyen et al, 2010

Two critical genes found to be up-methylated and under-expressed in ASD individuals are retinoic acid-related orphan receptor alpha (RORA) and B-cell lymphoma 2 (Bcl2).((Fig3)) RORA is reported to be involved in cerebellar development in murine models, and its inadequate expression has lead to a decrease in the absolute number of Purkinje cells, as well as a substantial decrease in dendrites and dendritic spines of those Purkinje cells.5 In addition, RORA is claimed to play a protective role against the deleterious effects of Beta-amyloid protein in the brain- a peptide implicated in Alzheimer's Disease.6 Similarly, Bcl2 has been reported to be involved with neuronal survival. For example, a study found that Bcl2 and p53 in sections of the parietal cortices of ASD individuals demonstrated abnormal apoptotic regulation. 7 Parietal cortex dysregulation may be responsible for deficits in language impairments observed in ASD, via audio/visual perception mechanisms,8 which might explain the reported link between certain ASD individuals and synesthesia,9 particularly auditory-visual synesthesia.

1.1c Environmental Factors

A study found that women living in the geographical area with the highest amount of pollutants such as lead, manganese, methylene chloride and other metals were almost 50 % more likely to give birth to a child with ASD. 10 There are also many studies that have found a correlation between exposure to certain factors such as thalidomide, misoprostol, valproic acid, and organophosphate insecticides during the early stages of pregnancy; as well as between maternal rubella, and ASD.11
There may also be an important effect of sex hormones, with estrogen being protective against autism; whereas testosterone has the opposite effect. ^^12 Both hormones are reported to modulate RORA expression (estrogen supports expression, testosterone inhibits expression). Moreover, RORA is thought to regulate the enzyme aromatase, which converts testosterone to estrogen, further decreasing the likelihood of females from developing of autism, and further increasing the likelihood for males. This gene-environment interaction explains why ASD is more common in males than in females.

1.2.Molecular Agents

1.2a Cytokines

A variety of cytokines are associated with ASD, all of which have a general commonality of being pro-inflammatory in function. For example, interleukin-6, Il-6, is suggested to be involved in the pathophysiology of ASD, producing behavioural symptoms by disturbing brain plasticity and overall function.13 Additionally, serum levels of interleukin-17, Il-17,secreted by T helper 17 cells mediating neutrophil-activating chemokines (e.g., CXCL1), have been reported to be significantly higher in ASD individuals compared with controls.14 Interestingly, Il-17 was also reported to be significantly higher in individuals with severe ASD compared with the mild or moderate subtype. Interleukin 17 is also associated with neuroinflammatory diseases such as multiple sclerosis. Furthermore, Th17 cells are suppressed by T regulatory cells, or Tregs, which have been reported to be reduced in 73 % of a sample population of individuals with ASD.15 Receptors for Th17 cells are found on macrophages and dendritic cells, which are believed to secrete interleukin 12 (Il-2), and interferon-gamma (IFNy), respectively.

It is suggested that Th17 receptors on these cells regulate T helper 1 cell differentiation, which mediate antibody class-switching, cytotoxicity, and phagocytosis. Macrophages and dendritic cells can also secrete interleukin 1 beta (Il-1b) and interleukin 12 (Il-12), which are also reported to be higher in the plasma of ASD individuals.16 Previously, it was thought that the over expression reported in autism was a result of B cell dysfunction; however, more recent studies suggest other cell types (i.e., T cells and antigen presenting cells) are more likely to be involved.17

1.2b Neurotrophic Factors, BDNF

Image Unavailable
Figure 4. A diagram of the effects of BDNF on different cell types.
Image Source: Duda et al., 2005

The most important factor implicated in autism is brain-derived neurotrophic factor (BDNF), which is found centrally as well as in peripherally. It is involved in neuronal survival and synaptic formation during brain development as well in subsequent brain plasticity(Fig4).18 It has been observed that BDNF levels increase in response to insult to the brain. Supporting this notion, increased serum levels of pro-inflammatory cytokines (responsive to injury or cytotoxic stress) such as Il-6 and Il2, were found in patients with elevated levels of BDNF. It is also implicated in the critical period of ocular dominance columns in cats, and in humans it promotes GABAergic cell maturation.19 A specific subtype of GABAergic cells are fast-spiking parvalbumin-positive basket cells (PV-cells), which are responsible for plasticity in certain brain regions (i.e., the visual cortex) in humans.20 These PV-cells have been shown to be disrupted in several murine models of ASD, suggesting an overall imbalance of excitation and inhibition.

1.3 Structural and Functional Differences in the Brain

1.3a Main Differences

A study examining brain tissue of children who had ASD and compared microglial densities to those of post-mortem controls demonstrated increased microglia in the ASD brains specifically in the visual cortex and fronto-insular cortices.21 High microglial densities were found in two of the control brains, but these were due to traumatic head and neck injury. This fact indicates that ASD mimics a physical injury, though the injury may actually originate organically, as a cause of environmental/toxic exposure, or a number of other possible ways. Importantly, these non-ASD brains only showed increased microglial densities in the fronto-insular cortex, as opposed to a more diffuse pattern of microglia overexpression found in the ASD brains. Increased microglia density was also observed in the dorsolateral prefrontal cortex (DLPFC).22
Additionally, elevated concentrations of glial fibrillary acidic protein (GFAP) are consistently reported in cerebellar, frontal, and parietal cortices of individuals with ASD compared with age-matched controls.23 Related to the cerebellum and thus to RORA, studies using voxel-based morphometry (VBM) have found cerebellar enlargements in young children with ASD.24

Image Unavailable
Figure 5. An illustration of the interactions between major cell types
in the immune and central nervous systems
Image Source: Onore et al., 2012

1.3b Behavioural Correlates

Atypically structured or functioning cerebella in ASD individuals may account for the majority, if not all, of the phenotypic characteristics of autism. These include motor impairments,25 abnormal gaze,26 deficits processing auditory cues in verbal communication (e.g., pitch),27 difficulty understanding and using language,28 and diruptions in higher-order emotional processing.29

It is important to notice that the neural-immune interrelations (Fig5) are absolutely vital to regular brain development and maintenance; thus, the mechanisms by which the immune and nervous systems work together to produce abnormal behaviour appear to be the most promising areas of investigation. As the vast majority of evidence regarding the pathophysiology and clinical presentation of ASD is correlational, an integrative and comprehensive understanding of the multifarious contributions of the disorder will continue to improve prognosis for those afflicted with the disorder.


Bibliography
1. Feng Y, Zhang F, Lokey LK, Chastain JL, Lakkis L, Eberhart D, Warren ST. (1995). Translational suppression by trinucleotide repeat expansion at FMR1. Science, 268:731–734.
2. Amir RE, Zoghbi HY. (2000). Rett syndrome: Methyl-CpG-binding protein 2 mutations and phenotype- genotype correlations. American Journal of Medical Genetics, 97:147–152.
3. Girirajan, S., Dennia, M.Y., … Eichler, EE. (2013). Refinement and discovery of new hotspots of copy-number variation associated with autism spectrum disorder. American Journal of Human Genetics, 92(2), 221-237.
4. Nguyen A, Rauch TA, Pfeifer GP, Hu VW. (2010). Global methylation profiling of lymphoblastoid cell lines reveals epigenetic contributions to autism spectrum disorders and a novel autism candidate gene, RORA, whose protein product is reduced in autistic brain. The FASEB Journal, 24:3036– 3051.
5. Hadj-Sahraoui N, Frederic F, Zanjani H, Delhaye-Bouchaud N, Herrup K, Mariani J. (2001). Progressive atrophy of cerebellar Purkinje cell dendrites during aging of the heterozygous staggerer mouse (Rora+/sg). Developmental Brain Research, 126:201–209.
6. Boukhtouche F, Vodjdani G, Jarvis CI, Bakouche J, Staels B, Mallet J, Brugg B. (2006). Human retinoic acid receptor-related orphan receptor a1 overexpression protects neurones against oxidative stress- induced apoptosis. Journal of Neurochemistry, 96, 1778–1789.
7. Fatemi, S.H., & Halt, A.R. Altered levels of Bcl2 and p53 proteins in parietal cortex reflect deranged apoptotic regulation in autism. (2001). Synapse, 42, 281-284.
8. Williams, J.H., Massaro, D.W., Peel, N.J., Bosseler, A., & Suddendorf, T. (2004). Visual-auditory integration during speech imitation in autism. Research in Developmental Disabilities, 25(6), 559-575.
9. Williams, J.H., Massaro, D.W., Peel, N.J., Bosseler, A., & Suddendorf, T. (2004). Visual-auditory integration during speech imitation in autism. Research in Developmental Disabilities, 25(6), 559-575.
10. Baron-Cohen, S., Johnson, D., Asher, J., Wheelwright, S., Fisher, S.E., Gregersen, P.K., & Allison, C. (2013). Is synesthaesia more common in autism? Molecular Autism, 4:40. doi:10.1186/2040-2392-4-40
11. Sifferlin, A. (2013). Prenatal exposure to pollution raises risk of autism in kids. Time, June 18.
12. Landrigan, P.J. (2010). What causes autism? Exploring the environmental contribution. Current Opinion in Pediatrics, 22(2), 219-225.
13. Hu, V.W. (2013). From genes to environment: Using integrative genomics to build a systems level understanding of autism spectrum disorders. Chidl Development, 84(1), 89-103.
14. Wei, H., Alberts, I., & Li, X. (2013). Brain Il-6 and autism. Neuroscience, 252(12), 320-325.
15. Yousef Al-Ayadhi, L., & Mostafa, G.A. (2012). Elevated serum levels of interleukin-17A in children with autism. Journal of Neuroinflammation, 9, 158.
16. Mostafa GA, Al Shehab A, Fouad NR. (2010). Increased frequency of CD4+CD25high regulatoryT cells in the peripheral blood of Egyptian children with autism. Journal of Clinical Neurology, 25, 328–335.
17. Mangan P.R., Harrington L.E., O’Quinn D.B., Helms W.S., Bullard D.C, … Elson C.O. (2006). Transforming growth factor-beta induces development of the Th 17 lineage. Nature, 441, 231–234.
18. Heuer, L.S., Rose, M., Ashwood, P., & Van de Water, J. (2012). Decreased levels of total immunoglobulin in children with autism are not a result of B cell dysfunction. Journal of Neuroimmunology, 251, 94-102.
19. Ricci, S., Businaro, R., Ippoliti, F., Lo Vasco, V.R., Massoni, F., Onofri, E., … Archer, T. (2013). Altered cytokine and BDNF levels in autism spectrum disorder. Neurotoxicity Research, 24(4), 491-501.
20. Huang Z.J., Kirkwood A., … Pizzorusso T. (1999). BDNF regulates the maturation of inhibition and the critical period of plasticity in mouse visual cortex. Cell, 98(6), 739–755.
21. LeBlanc, J.J., & Fagiolini, M. (2011). Autism: A critical period disorder? Neuronal Plasticity, 921680. Doi: 10.1155/2011/921680.
22. Tetreault, N.A., Hakeem, A.Y., Jiang, S., Willias, B.A., Allman, E., … Allman, J.M. (2012). Microglia in the cerebral cortex in autism. Journal of Autism and Developmental Disorders, 42, 2569-2584.
23. Rodriguez, J.I., & Kern, J.K. (2011). Evidence of microglial activation in autism and its possible role in brain underconnectivity. Neuron Glia Biology, 7(2), 205-213.
24. Laurence J.A., & Fatemi S.H. (2005). Glial fibrillary acidic protein is elevated in superior frontal, parietal and cerebellar cortices of autistic subjects. Cerebellum, 4, 206–210.
25. Scott, J.A., Schumann, C.M., Goodlin-Jones, B.L., & Amaral, D.G. (2009). A comprehensive volumetric analysis of the cerebellum in children and adolescents with autism spectrum disorder. Autism Research, 2(5), 246–257.
26. Ozonof,f S., Young, G.S., Goldring, S., Greiss-Hess, L., Herrera, A.M., … Steele, J. (2008). Gross motor development, movement abnormalities, and early identification of autism. Journal of Autism and Developmental Disorders, 38,6 44–656.
27. Brettler, S.C., Fuchs, A.F., & Ling, L. (2003). Discharge patterns of cerebellar output neurons in the caudal fastigial nucleus during head-free gaze shifts in primates. Annals of the New York Academy of Sciences, 1004,61–68.
28. Shriberg, L., Paul, R., Black L., & van Santen, J. (2011). The Hypothesis of Apraxia of Speech in Children with Autism Spectrum Disorder. Journal of Autism and Developmental Disorders, 41(4), 405–426.
29. Ackermann, H., Wildgruber, D., Daum, I., & Grodd, W. (1998). Does the cerebellum contribute to cognitive aspects of speech production? A functional magnetic resonance imaging (fMRI) study in humans. Neuroscience Letters, 247(2–3), 187–190.
30. Steinlin, M. (2007). The cerebellum in cognitive processes: Supporting studies in children. Cerebellum, 6, 237–241.

Add a New Comment
Unless otherwise stated, the content of this page is licensed under Creative Commons Attribution-ShareAlike 3.0 License