Convergence of spectrums: neuronal gene network states in autism spectrum disorder

Abstract

Autism spectrum disorder (ASD) is a prevalent neurodevelopmental disorder characterized by social deficits and restrictive and/or repetitive behaviors. The breadth of ASD symptoms is paralleled by the multiplicity of genes that have been implicated in its etiology. Initial findings revealed numerous ASD risk genes that contribute to synaptic function. More recently, genomic and gene expression studies point to altered chromatin function and impaired transcriptional control as additional risk factors for ASD. The consequences of impaired transcriptional alterations in ASD involve consistent changes in synaptic gene expression and cortical neuron specification during brain development. The multiplicity of genetic and environmental factors associated with ASD risk and their convergence onto common molecular pathways in neurons point to ASD as a disorder of gene regulatory networks.

Figure 1.. Converging pathways in ASD.

Scheme shows the two major pathways implicated in ASD risk based on genomic studies and gene expression analysis of affected individuals. (Left) Dysregulation of gene expression at the level of chromatin modifications, chromatin remodeling, regulation of transcription, and RNA splicing, as well as (right) alterations in synapse development and function are strongly associated with ASD risk. Recent data suggest a convergence of the two pathways in ASD pathology, where changes in neuronal gene expression regulation during fetal brain development preferentially affect genes important for synapse function and neuronal differentiation, and conversely, changes in genes important for synaptic function and neuronal specification indirectly affect neuronal gene expression regulation.

Figure 2.. Robustness of cell/neuron differentiation during development.

Modified scheme of Waddington’s “epigenetic landscape” [53] illustrates cell differentiation during development. (A) Multipotent stem cells and (B) neuronal progenitor cells (white circle) follow a robust developmental trajectory or “canalization” towards a specific outcome. In this “epigenetic landscape”, distinct extrinsic and intrinsic signals lead to the establishment of “valleys” and “ridges” that ensure robustness and guide the differentiation processes towards distinct differentiated cell types (A) or neuronal subtypes (B).

Figure 3.. Epigenetic landscape of normal brain development and ASD.

(A) Modified scheme from Huang et al, 2009 [53] of an epigenetic landscape during brain development. The landscape is a schematic projection of a complex gene network into a two-dimensional state space. The y axis represents the relative stability of individual cell states where higher positions indicate less stability. The valleys represent stable attractor states that occupy the low-energy stable basin and are resistant to perturbations. Normal developmental trajectory (blue) progresses from back to front towards a stable attractor state, which represents a distinct neuronal state, and is prevented from entering unused “abnormal attractors” (red dashed circle) along the path due to epigenetic barriers (orange area). Mutations or environmental insults can lower this barrier, thus opening access to unused attractors that encode an abnormal phenotype = ASD attractor state (red dashed arrow). Alternatively, the ASD gene network state may reflect an unstable neuronal state that hinders the formation of stable neuronal networks. (B) Model of ASD network states and their potential reversibility. Scheme shows highly simplified version of proposed model for normal (blue) and ASD (red) gene network states. The y axis represents the relative stability of individual cell states where higher positions indicate less stability. The x axis represents the specific space coordinate of a given neuronal network state. Future potential therapies could be aimed at trying to reverse symptoms of ASD by targeting the ASD network states (red, novel ASD attractor state or unstable state) followed by their conversion into a normal stable neuronal network state (blue).