Autism spectrum disorders pathogenesis: Toward a comprehensive model based on neuroanatomic and neurodevelopment considerations

Abstract

Autism spectrum disorder (ASD) involves alterations in neural connectivity affecting cortical network organization and excitation to inhibition ratio. It is characterized by an early increase in brain volume mediated by abnormal cortical overgrowth patterns and by increases in size, spine density, and neuron population in the amygdala and surrounding nuclei. Neuronal expansion is followed by a rapid decline from adolescence to middle age. Since no known neurobiological mechanism in human postnatal life is capable of generating large excesses of frontocortical neurons, this likely occurs due to a dysregulation of layer formation and layer-specific neuronal migration during key early stages of prenatal cerebral cortex development. This leads to the dysregulation of post-natal synaptic pruning and results in a huge variety of forms and degrees of signal-over-noise discrimination losses, accounting for ASD clinical heterogeneities, including autonomic nervous system abnormalities and comorbidities. We postulate that sudden changes in environmental conditions linked to serotonin/kynurenine supply to the developing fetus, throughout the critical GW7 – GW20 (Gestational Week) developmental window, are likely to promote ASD pathogenesis during fetal brain development. This appears to be driven by discrete alterations in differentiation and patterning mechanisms arising from in utero RNA editing, favoring vulnerability outcomes over plasticity outcomes. This paper attempts to provide a comprehensive model of the pathogenesis and progression of ASD neurodevelopmental disorders.

RNA epitranscriptomics dysregulation: A major determinant for significantly increased risk of ASD pathogenesis

“…In our previous work ( Beopoulos et al, 2022 ), we had explored the possible impacts of increased placental release of serotonin, subsequent to sustained maternal low-grade inflammation in early to mid-pregnancy, upon the probability of ASD pathogenesis in the offspring and found strongly corroborating evidence in a multiplicity of reports. Hence, although subject to numerous caveats involving fetal genotypes and environmental factors affecting maternal wellbeing, maternal low-grade systemic inflammation, reported be about 25% in a sample of adult US women ( Ford et al, 2004 ), particularly during early and mid-pregnancy, seems to be a major determinant for significantly increased risk of ASD pathogenesis.…”

“…Another consequence of altered early developmental programs specific to ASD is the deregulation of layer formation and layer-specific neuronal migration in prenatal cerebral cortex development ( Beopoulos et al, 2022 ). Moreover, the gene expression profiles that, in neurotypical development (ND), distinguish the frontal from the temporal cortex are significantly attenuated ( Johnson et al, 2009 ), implying that transcriptional and splicing dysregulation are among the underlying mechanisms of neuronal dysfunction in this disorder.…”

“…Serotonin (5-HT) is a key regulator of neural circuit development by modulating neuronal proliferation, migration and differentiation. Most of its effects are mediated by the 14 5-HT receptors, all of which are G protein-coupled, with the exception of the ionotropic 5-HT type 3A receptor (5-HT3A) which is responsible for rapid neuronal activation ( Takumi et al, 2020 ; Beopoulos et al, 2022 ). Dysregulation of the 5-HT system is involved in the development of several neuropsychiatric disorders, including intellectual disability, autism, depression and anxiety ( Kinast et al, 2013 ; Brummelte et al, 2017 ; Velasquez et al, 2017 ).…”

“…In mammals, during early cortical development and up to 16 weeks of gestation (GW16), 5-HT is of maternal and/or placental origin ( Cote et al, 2007 ; Bonnin and Levitt, 2011 ; Beopoulos et al, 2022 ), whereas later, serotonergic afferents invade the cortex and the developing fetus initiates its own 5-HT production ( Gaspar et al, 2003 ; Vitalis and Rossier, 2011 ; Budday et al, 2015 ; Nowakowski et al, 2016 ; Beopoulos et al, 2022 ). Importantly, 5-HT signaling is influenced by numerous epigenetic and genetic factors, as well as by perinatal stress ( Papaioannou et al, 2002 ; Provenzi et al, 2016 ), infection and inflammation ( Winter et al, 2009 ; Gupta et al, 2015 ), 5-HT metabolism and storage, ( Popa et al, 2008 ) and genetic alterations ( Pluess et al, 2010 ; Karg et al, 2011 ).…”

“…However, little progress has been made toward the causes for laminar-specific excitatory and inhibitory cortical circuits disruption ( Watts, 2008 ; Prem et al, 2020 ). Recent genetic studies have also identified that risk genes substantially converge in the development of the cortex between the 8 and 24th week of gestation (GW8-24) ( Courchesne et al, 2019 ; Beopoulos et al, 2022 ). However, the majority of animal studies on ASD focus primarily on postnatal development and defects in synaptic transmission, rather than on early developmental processes guiding central nervous system (CNS) formation, such as cell differentiation, proliferation, migration, and arborization.…”