Neurodevelopmental Hypothesis about the Etiology of Autism Spectrum Disorders

Abstract

Previous models or hypotheses of autism spectral disorder (ASD) failed to take into full consideration the chronological and causal developmental trajectory, leading to the emergence of diverse phenotypes through a complex interaction between individual etiologies and environmental factors. Those phenotypes include persistent deficits in social communication and social interaction (criteria A in DSM-5), and restricted, repetitive patterns of behavior, interests, or activities (criteria B in DSM-5). In this article, we proposed a domain-general model that can explain criteria in DSM-5 based on the assumption that the same etiological mechanism would trigger the various phenotypes observed in different individuals with ASD. In the model, we assumed the following joint causes as the etiology of autism: (1) Hypoplasia of the pons in the brainstem, occurring immediately following neural tube closure; and (2) Deficiency in the GABA (γ-aminobutyric acid) developmental switch during the perinatal period. Microstructural abnormalities of the pons directly affect both the structural and functional development of the brain areas strongly connected to it, especially amygdala. The impairment of GABA switch could not only lead to the deterioration of inhibitory processing in the neural network, but could also cause abnormal cytoarchitecture. We introduced a perspective that atypical development in both brain structure and function can give full explanation of diverse phenotypes and pathogenetic mechanism of ASD. Finally, we discussed about neural mechanisms underlying the phenotypic characteristics of ASD that are not described in DSM-5 but should be considered as important foundation: sleep, global precedence, categorical perception, intelligence, interoception and motor control.

Symptom improvement in children with autism spectrum disorder following bumetanide administration is associated with decreased GABA/glutamate ratios

“…ASD can be reliably diagnosed at 24 months or even as early as 18 months of age 3 , and is a life-long condition. Although the molecular and neural mechanisms underlying ASD remain largely unknown, a previous study suggested that ASD may result from alteration in brain development during early life, such as the excitatory-inhibitory (E-I) imbalance in the autistic brain can affect the sensory, memory and emotional systems 4 , indicating the necessity of early intervention. Without directly monitoring the neuronal E-I balance, current behavioural interventions for ASD at preschool age are mainly behavioural intervention, including parentsmediate Early Start Denver Model and the Applied Behaviour Analysis 5 .…”

A Systematic Review of the Valproic-Acid-Induced Rodent Model of Autism

“…Similar timing effects of VPA exposure are also observed in rodents [20,21], with effective treatments likely being associated with processes related to neural tube closure [22]. Hypoplasia of the pons in the brainstem, occurring immediately following neural tube closure, has been proposed as one of the unifying causes of autism phenotype [23]. The VPA rodent model appears to possess face validity and construct validity to model human ASD, as VPAexposed rodents seem to express a similar superficial behavioural phenotype as people with ASD [24].…”

Evidence for Brainstem Contributions to Autism Spectrum Disorders

“…Historically, the brainstem was at the center of the first brain-based hypothesis of ASD, which theorized that this early-developing neural structure was responsible for the behavioral features of autism ( Rimland, 1964 ). Recently, ASD symptomatology was ascribed to the hypoplasia of the brainstem’s pons, supporting the neurodevelopmental model of autism and the critical role of the brainstem in ASD behaviors ( Inui et al, 2017 ).…”

“…These processes lead to an integrative brain where both structure and function of the more complex cortical circuitry rely on the fidelity of the ancestral brain wiring and the efficacy of “lower level” processing. Even a minor disruption of the early neurodevelopmental events could lead to altered brain connectivity and function, affecting integrity of the lower level processing first, and, as a consequence, perturbing the function of the higher order neurocircuitry ( Rodier, 2002 ; Hammock and Levitt, 2006 ; Thompson and Levitt, 2010 ; Inui et al, 2017 ). In all, the brainstem is uniquely positioned to be an initiating link in the unfolding of the hierarchical brain development, suggesting its implication in the whole spectrum of functions that the mammalian brain performs, including the functions traditionally attributed to higher order circuitry.…”

“…Autism spectrum disorder (ASD) is a lifelong condition affecting one in 59 children ( Baio et al, 2018 ). This condition is clinically heterogeneous and has neurodevelopmental origin ( Inui et al, 2017 ; Piven et al, 2017 ; Shen and Piven, 2017 ). As suggested by human genetics and studies in animal models, early neurodevelopmental alterations may give rise to diverse ASD behaviors (for a review see Lai et al, 2014 ; Chen et al, 2015 ).…”