Fundamental Elements in Autism: From Neurogenesis and Neurite Growth to Synaptic Plasticity

Abstract

Autism spectrum disorder (ASD) is a set of neurodevelopmental disorders with a high prevalence and impact on society. ASDs are characterized by deficits in both social behavior and cognitive function. There is a strong genetic basis underlying ASDs that is highly heterogeneous; however, multiple studies have highlighted the involvement of key processes, including neurogenesis, neurite growth, synaptogenesis and synaptic plasticity in the pathophysiology of neurodevelopmental disorders. In this review article, we focus on the major genes and signaling pathways implicated in ASD and discuss the cellular, molecular and functional studies that have shed light on common dysregulated pathways using in vitro, in vivo and human evidence. Highlights Autism spectrum disorder (ASD) has a prevalence of 1 in 68 children in the United States.ASDs are highly heterogeneous in their genetic basis.ASDs share common features at the cellular and molecular levels in the brain.Most ASD genes are implicated in neurogenesis, structural maturation, synaptogenesis and function.

Keywords: ASD; autism; dendrite growth; developmental neurobiological disorders; neurogenesis; neuron morphogenesis; synapse; synaptic plasticity.

Figure 1

Radial-glia guided neuronal migration. Radial glia cells (green), extend long basal process to the pial surface, with their somas located in the ventricular zone (VZ). Neurons (blue) are born in the VZ and migrate along radial glia fibers. The cortical plate is formed in an inside-out fashion such that later-born neurons that will reside in the upper layers pass through earlier-born neurons in deeper layers (lighter blue shading). The marginal zone contains horizontally-oriented Cajal-Retzius cells (orange) which release the extracellular signaling glycoprotein Reelin.

Figure 2

Stages of neurite growth. Representative neocortical mouse pyramidal neuron morphologies at different early postnatal time points during development. P = postnatal.

Figure 3

Synaptic proteins and signaling pathways linked to autism spectrum disorder (ASD). ASD-linked synaptic proteins and signaling pathways that relate to synaptogeneis and synaptic function. Stars mark ASD-linked proteins discussed in this review article. Abbreviations: AMPAR, AMPA receptor; NMDAR, NMDA receptor; mGluR, metabotropic glutamate receptor; PSD-95, postsynaptic scaffolding protein 95 kDa; CNTNAP2, contactin-associated protein-like 2 gene; PI3K, phosphoinositide-3 kinase; Ras, RhoGTPase; GTP, Guanosine-5′-triphosphate; NF1, Neurofibromatosis type 1; PTEN, phosphatase and tensin homolog; Akt, serine/threonine specific kinase; TSC, tuberous sclerosis complex; mTOR, mammalian target of rapamycin; Raf, Rapidly accelerated fibrosarcoma serine threnonine kinase, MEK, Mitogen-activated protein kinase kinase; ERK, extracellular signal–regulated kinase; 40S, ribosomal subunit; FMRP, fragile-X mental retardation protein; CREB, cAMP response element-binding protein; CBP, CREB binding protein; MeCP2, methyl CpG binding protein 2; KIDLIA, KIAA2022 gene with intellectual disability (ID) and language impairment in autism; P, phosphate group.