By Adriana Ramos Calvo
Autism Spectrum Disorders (ASDs) are a group of neurodevelopmental disorders that impact normal communication and social interaction, impairing cognitive functions and causing atypical behaviors through the decline of perception and judgment (McPartland and Volkmar, 2012). ASDs, which include: autistic disorder, pervasive developmental disorder-not otherwise specified (PDD-NOS) and Asperger’s disorder, are multi-factorial and multi-symptomatic psychiatric disorders that can be diagnosed entirely based on the patient’s behavior (Markkanen, Meyer and Dianov, 2016). A lot of effort, however, has been put towards studying the neuroanatomical distinctions between ASD sufferers and neurotypical controls (Donovan and Basson, 2016).
Albeit the etiology of Autism Spectrum Disorders is unclear, there is a strong suggestion that the cause of this disease is the cumulation of disruptions in both immune regulation and glial cell function and neural circuitry. The former has been predominantly studied in the context of the activation of immune pathways by exogenous stimuli. Nonetheless, considering the modern understanding of the relevance of the immune system and glial cell in normal neurodevelopment, recent studies hypothesize that the phenotype of the autistic brain should represent abnormalities of glial or immune processes that entirely function in normal brain development, resulting in a dysfunction of the neural network (Ziats, Edmonson and Rennert, 2015).
A recent study carried out by Cambridge University and King’s College London using pluripotent stem cells (iPSCs) showed that the early development of brain cells from autistic patients differed from that of their neurotypical counterparts (Adhya et al., 2020). The researchers used hair samples from nine autistic people and six controls, which were treated with a sequence of growth factors to drive the hair cells to become nerve cells like those found in the midbrain region. iPSCs retain the genetic identity of the patient from whom the sample was taken and re-start their development, allowing the study of early brain development in a non-invasive, ethical way. The cells’ appearance and RNA sequence were studied at various developmental stages. Autistic brain cells did not form the indicative shape of typically developing neurons and, furthermore, did not express sufficient levels of key developmental genes. In later stages, autistic and control cortical neurons differed significantly and, on the contrary, midbrain neurons – which are not involved in the autistic disorder – did not show relevant differences (Adhya et al., 2020).
There is a limited but growing body of evidence that shows brain inflammation in addition to immune dysfunction in young ASD patients. A novel report showed overexpression of the proinflammatory cytokines IL-18 and TNF, as well as the anti-inflammatory cytokine IL-37 in the amygdala and dorsolateral prefrontal cortex of ASD patients as compared to the neurotypical controls. An overexpression of IL-18R, that functions as a receptor for both IL-18 and IL-37, was also observed in the same brain areas. Moreover, neurotensin (NT)-stimulated secretion and gene expression of IL-1β and CXCL8 was proven to be inhibited by IL-37 in cultured human microglia, the resident macrophage cells. The report also showed that neurotensin, IL-1β, and TNF increased gene expression of IL-37 in these microglia. These crucial discoveries support the development of IL-37 as a potential treatment for ASD since NT and IL-37 are necessary for the activation of microglia and the inhibition of inflammation, respectively (Tsilioni et al., 2019).
Other neuroimaging studies have also shown that the brain of young children (between 2 and 4 years old) who suffer from ASD is, generally, more voluminous than the brain of their neurotypical counterparts. This overgrowth cannot be observed in older patients (5 to 6 years old), after the convergence of both groups’ growth curves. These findings suggest that there are differences in all the phases of brain maturation between ASD sufferers and the controls: a period of overgrowth during early toddlerhood, followed by a phase of slowed down maturation during the rest of the childhood and a potentially hasty decline during adult life (Ecker, Schmeisser, Loth and Murphy, 2017).
On the whole, the multiple studies mentioned show that there are numerous symptoms and comorbidities derived from Autism Spectrum Disorders, however, a consistent pattern of pathologies is yet to be found. A study carried out by the Department of Psychiatry and Behavioral Sciences of the University of California suggests that well-characterized brain tissue as well as defining the phenotypes of larger samples of children will be needed to clarify the neuroanatomy of autism (Amaral, Schumann and Nordahl, 2008).
Adhya, D., Swarup, V., Nagy, R., Dutan, L., Shum, C., Valencia-Alarcón, E., Jozwik, K., Mendez, M., Horder, J., Loth, E., Nowosiad, P., Lee, I., Skuse, D., Flinter, F., Murphy, D., McAlonan, G., Geschwind, D., Price, J., Carroll, J., Srivastava, D. and Baron-Cohen, S., 2020. Atypical Neurogenesis in Induced Pluripotent Stem Cells From Autistic Individuals. Biological Psychiatry,.
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Donovan, A. and Basson, M., 2016. The neuroanatomy of autism – a developmental perspective. Journal of Anatomy, 230(1), pp.4-15.
Ecker, C., Schmeisser, M., Loth, E. and Murphy, D., 2017. Neuroanatomy and Neuropathology of Autism Spectrum Disorder in Humans. Translational Anatomy and Cell Biology of Autism Spectrum Disorder, pp.27-48.
Markkanen, E., Meyer, U. and Dianov, G., 2016. DNA Damage and Repair in Schizophrenia and Autism: Implications for Cancer Comorbidity and Beyond. International Journal of Molecular Sciences, 17(6), p.856.
McPartland, J. and Volkmar, F., 2012. Autism and related disorders. Neurobiology of Psychiatric Disorders, pp.407-418.
Tsilioni, I., Patel, A., Pantazopoulos, H., Berretta, S., Conti, P., Leeman, S. and Theoharides, T., 2019. IL-37 is increased in brains of children with autism spectrum disorder and inhibits human microglia stimulated by neurotensin. Proceedings of the National Academy of Sciences, 116(43), pp.21659-21665.
Ziats, M., Edmonson, C. and Rennert, O., 2015. The autistic brain in the context of normal neurodevelopment. Frontiers in Neuroanatomy, 9.