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.

Keywords: RNA editing; autism spectrum disorder (ASD); autonomic nervous system (ANS); kynurenine metabolites; maternal inflammation; neurodevelopment; serotonin; synaptic pruning.

FIGURE 1

Fear circuit in the amygdala. Cortical and thalamic projections conveying somatosensory (US) and auditory (CS) information are targeting the lateral amygdala (LA), a major location of initial synaptic plasticity. Somatostatin (SST)/neuropeptide Y (NPY)/γ-aminobutyric acid (GABA) neurons may inhibit pyramidal neurons by activation of postsynaptic Y1 and presynaptic Y2 receptors reducing CS-related activation and fear learning. Similarly, SST/NPY neurons in the basolateral nucleus (BLA) may have additional Y1 receptor-dependent inhibiting effects. The role of NPYergic afferent and efferent projections of the basolateral complex (LA and BLA) is not yet clear. Fear related stimuli reach the central amygdala (CEA) also via mediodorsal intercalated neurons (ITCd) to the centrolateral subdivision (CEl) or directly via projections from the BLA to the centromedial subdivision (CEm). NPY neurons may modulate afferent and efferent signals locally in the CEl or via inhibitory connections between CEl and CEm, probably by Y2 receptors. However, the main processing occurs in the CEm (expressing Y1 and Y2 receptors) by (1) local inhibitory SST/NPY/GABA neurons, (2) by NPY/GABA afferents originating from the BNST, and (3) by NPY axon terminals originating from neurons of the main intercalated nucleus (Im). The latter projection consisting of NPY/dopamine receptor D1 (D1R)/GABA neurons in the Im is considered to play an essential role in fear extinction by providing a marked increase in feed-forward inhibition from the BLA to the CEm. Lastly, efferents from the CEm may be further modulated by NPY along the stria terminalis (st) or even in the bed nucleus of the stria terminalis (BNST), both by local interneurons and by bi-directional projections connecting the CEm with the BNST. AStr, amygdala-striatal transition zone; En, entorhinal cortex; Pir, piriform cortex; BF, basal forebrain; CEc, capsular subdivision of the central amygdala nucleus. Figure from Tasan et al. (2016), obtained by Elsevier (No. 5410821023270) under a creative commons license 3&4.

FIGURE 2

(A) Very early cerebral cortex development. Sketch of the mammalian neural tube showing the proneuromeric compartments. The neural tube will develop to form the brain and spinal cord. It is divided to the alar plate (colored in blue) that will later generate neurons associated with sensory functions (somatic and visceral), and the basal plate (red) that will primarily contain motor neurons. The notochord, of mesodermal origin (green) provides directional cues to the surrounding tissues. The telencephalic vesicle (highlighted in darker blue) grows out of the alar plate of the secondary prosencephalon. (B) Very early cerebral cortex development. Section through the secondary prosencephalon at the level of the black line in (A) shows the optic vesicles and the telencephalic vesicles; the telencephalic vesicles consist of pallial and subpallial territories. (C) Two organizers direct the patterning of the pallium: the hem, at the border of the roof plate and the prospective hippocampus, and the antihem, at the corticostriatal junction near the prospective olfactory cortex. The morphogen molecules segregated by these organizers form overlapping gradients (solid and dashed arrows) that pattern the pallium in four sectors: medial, dorsal, lateral, and ventral pallial sectors. The distinction of two parts on the MPall sector corresponding to allocortex (hippocampus) and the adjacent mesocortex (marked with “?”) is hypothesized based on architectonic analysis of adult rats and primates. DPall, dorsal pallium; LPall, lateral pallium; MPall, medial pallium; VPall, ventral pallium. Figure from García-Cabezas and Zikopoulos (2019), obtained by Elsevier (No. 5410821023270) under a creative commons license 3&4.

FIGURE 3

Schematic representation of the human brain development timeline. The dotted arrows designate a reduction in the rate of neurogenesis. Figure adapted from Stagni et al. (2015), obtained by Elsevier (No. 5410821023270) under a creative commons license 3&4.

FIGURE 4

Maturation and differentiation in the cortex. (Left) Schematic representing radial glia maturation from neuroepithelial stem cells (NESCs), followed by their differentiation into astrocytes. (Right) Schematic represents sequential production of cortical layers from radial glia. Human cortical development involves an expanded diversity of radial glia with distinct maturation trajectories (left). Neurogenesis in the human cortex occurs in the ventricular zone early in development and progressively shifts toward the outer subventricular zone (OSVZ). The development of the OSVZ is not homogeneous across prospective cortical areas in human fetuses, but increases from prospective mesocortical to prospective isocortical areas (Barbas and García-Cabezas, 2016). IPCs, intermediate progenitor cells; ISVZ, inner subventricular zone; LI–VI, cortical layer I–VI; NESCs, neuroepithelial stem cells; oRG, outer radial glia; OSVZ, outer subventricular zone; SVZ, subventricular zone; tRG, truncated radial glia; vRG, ventricular radial glia; VZ, ventricular zone; WM, white matter. Figure adapted from Cadwell et al. (2019).

FIGURE 5

The human cerebral cortex at 28 weeks postmenstrual age (PMA; 8 weeks before birth). A coronal section is shown on the left; the inset box on the right provides details of the developmental processes. The ventricular zone (VZ) and subventricular zone (SVZ) constitute the germinal matrices where cell division occurs. The first generations of cells are generated in the VZ, the later generations in the SVZ. The SVZ is a structure that expanded during phylogeny; it is especially large in primates. The radial glial cells span their shafts between the germinal layers and the outer layer of the cortex [marginal zone (MZ)]. The first-generation neurons have migrated to the subplate (SP) and participate in the functional fetal cortex; later generations of neurons migrate to the cortical plate (CoP). Figure from Hadders-Algra (2018a), see Luhmann et al. (2018) for a detailed review, obtained by Elsevier (No. 5410821023270) under a creative commons license 3&4.

FIGURE 6

Early stages of development of the human cerebral cortex in relation with 5-HT afferents. In human, intense proliferation of the neuroepithelium and formation of the preplate (PP) take place around GW5 and GW6–7, respectively. By GW8–10, PP is split by the migration of the first pyramidal neurons. Cajal-Retzius cells (C-R) will remain in the marginal zone (MZ, presumptive layer I) while sub-plate neurons (SP) will be positioned below the cortical plate (CP). In addition, around GW10, another source of progenitors arises: the outer radial glial (oRG) cells that do not maintain contacts with the apical surface. Monoaminergic axons and thalamo-cortical axons (TC) are already found in the MZ and in the intermediate zone (IZ), respectively. By GW16, SP cells occupy a large proportion of the cortical anlage and oRG are still producing a high number of neurons. Interneurons migrating first tangentially and later radially to the pial surface, incorporate into the CP. The cortical structure is vascularized very early and carries platelets and mast cells that could provide 5-HT to the developing embryo. During the initial phase of cortical development, 5-HT is mainly synthesized in the placenta while later produced by serotonergic neurons of the embryo. The colored lower bars indicate the times at which different factors (maternal and environmental; 5-HT of placental origin, 5-HT produced by the embryo itself) could affect the development (figure from Vitalis and Verney, 2017), obtained by Elsevier (No. 5410821023270) under a creative commons license 3&4.

FIGURE 7

Maternal, placental, genetic, and pharmacological conditions determining the amount of serotonin supply to the developing telencephalon. The placenta provides tryptophan to the embryo but can also convert it into 5-HTP (5-hydroxytryptamine) or further into serotonin (5-HT) via various maternal metabolic enzymes. In addition, 5-HT from maternal sources could be taken up by the placenta where the serotonin transporter (SERT) is also expressed. During early embryonic stages, 5-HT could thus be directly delivered to the developing embryo. In the mouse, after E15-E16 (approximately GW 16 in humans), when 5-HT axons of the hindbrain reach the cortex, 5-HT could act on various target cells expressing selected arrays of 5-HT receptors. At this stage, 5-HT could also be taken up and stored by thalamocortical afferents (TC) and released after specific stimulation. In addition, 5-HTP is provided by Tph2 (tryptophan hydroxylase type 2) and AADC (aromatic amino acid decarboxylase) containing neurons that synthetize 5-HT. The large downward arrow on the left in this diagram, adapted from Bonnin and Levitt (2011), points to the maternal conditions that are best known to interfere with 5-HT availability to the embryo. Inhibitors of 5-HT uptake (SSRIs) which affect SERT function at all levels are indicated by a thick orange arrow while known genetic polymorphisms or epigenetic alterations (methylations) which impact serotonin supply are indicated by a star. The major catabolic enzymes of 5-HT are MAO (monoamine oxidases) and tryptophan hydroxylase type 1 (Tph1). Adapted from Bonnin and Levitt (2011) and Vitalis and Verney (2017), obtained by Elsevier (No. 5410821023270) under a creative commons license 3&4.

FIGURE 8

(A) Mechanisms underlying focal organization and minicolumn distribution in the cortex. During normal cortical development, radial glial neural stem and progenitor cells (NSCs; black) located in the ventricular zone, with radial processes extending to the pial surface of the neural epithelium, can undergo symmetrical divisions to produce more radial glial NSCs (brown) or asymmetric divisions (A) to maintain the NSC pool and generate committed neural progenitors (pink); (B) the latter migrate toward the pial surface on the radial scaffold, where they differentiate into projection neurons. This process continues with different classes of neurons (pink, green) being produced in successive waves over developmental time. Hence, different neuronal types are grouped together in different cortical layers (C). GABAergic interneurons (orange) migrate into the neuroepithelium (B), and integrate into the circuitry (C). At the end of this process, projection neurons are organized in radial minicolumns. Figure adapted from Donovan and Basson (2017), obtained by Elsevier (No. 5410821023270) under a creative commons license 3&4.

FIGURE 9

Potential mechanisms underlying focal disorganization and altered minicolumn distribution in ASD cortex. Focal disruptions may be the result of a combination of early genetic, epigenetic changes or environmental changes affecting neural stem and progenitor cell such that the resulting neuronal progenitors have defects in (I) differentiation (II) or migration (III) causing them to adopt the wrong fate (IV), or end up in an in appropriate position in the brain (V). The end result is a cortex with apparent disorganization of neuronal cell types and distorted cell densities. Figure adapted from Donovan and Basson (2017), obtained by Elsevier (No. 5410821023270) under a creative commons license 3&4.

FIGURE 10

Synapse formation and pruning in neurotypical development. Starting from birth until adolescence, the synaptic pruning process, preceded by synaptic overgrowth, optimizes the neurological network by removing redundant and weak connections as defined by the learning process, effectively making the brain more efficient. Adults have been found to have approximately 41% fewer neurons than newborns (Abitz et al., 2007). Figure adapted from Conel (1939), obtained by Elsevier (No. 5410821023270) under a creative commons license 3&4.

FIGURE 11

(A) Synaptic pruning in brain development serves to refine communication between functional areas by improving the signal-to-noise ratio. At early postnatal stage, Cajal-Retzius cells (C-R) that express 5-HT3A, respond to 5-HT by releasing reelin which, through the activation of the integrin signaling pathway, induces pruning of apical dendrites of pyramidal neurons (Pyr). (B) Pruning reduces unnecessary cross-talk with neighboring nodes (blue and red in typical development, Panel TD). However, in the presence of too many overlapping connections, distinct signals from neighboring communities may compete and interfere with each other, effectively creating noise and “confusion” within the network (blue and red in autism spectrum disorder, Panel ASD), while negatively affecting the development of long-distance connectivity, such as those between fronto-parietal regions for higher-order executive functions [adapted from Belmonte et al. (2004), Just et al. (2012), and Vitalis and Verney (2017)], obtained by Elsevier (No. 5410821023270) under a creative commons license 3&4.