Dysregulation of Multiple Signaling Neurodevelopmental Pathways during Embryogenesis: A Possible Cause of Autism Spectrum Disorder

Abstract

Understanding the autistic brain and the involvement of genetic, non-genetic, and numerous signaling pathways in the etiology and pathophysiology of autism spectrum disorder (ASD) is complex, as is evident from various studies. Apart from multiple developmental disorders of the brain, autistic subjects show a few characteristics like impairment in social communications related to repetitive, restricted, or stereotypical behavior, which suggests alterations in neuronal circuits caused by defects in various signaling pathways during embryogenesis. Most of the research studies on ASD subjects and genetic models revealed the involvement of mutated genes with alterations of numerous signaling pathways like Wnt, hedgehog, and Retinoic Acid (RA). Despite significant improvement in understanding the pathogenesis and etiology of ASD, there is an increasing awareness related to it as well as a need for more in-depth research because no effective therapy has been developed to address ASD symptoms. Therefore, identifying better therapeutic interventions like “novel drugs for ASD” and biomarkers for early detection and disease condition determination are required. This review article investigated various etiological factors as well as the signaling mechanisms and their alterations to understand ASD pathophysiology. It summarizes the mechanism of signaling pathways, their significance, and implications for ASD.

A bibliometrics analysis and visualization of autism spectrum disorder

“…Nearly three-fourths of ASD patients have more than 16 medical, mental, or neurological diseases, such as attention deficit hyperactivity disorder, intellectual disorder, self-injurious behavior, and sleep disorder, making it the main cause of mental disability in children under 5 years old ( 9 , 10 ). In addition, ASD currently lacks specific diagnostic markers and targeted treatment methods, which causes a greater economic burden to individuals, their families, and society ( 11 ).…”

Illuminating links between cis-regulators and trans-acting variants in the human prefrontal cortex

“…Reduced levels of the nuclear receptor TF RORA have been observed in the prefrontal cortex and cerebellar neurons of individuals with autism spectrum disorder (ASD) [ 36 ], and retinoic acid signaling pathways have been reported to be disrupted in ASD-afflicted individuals [ 37 ]. The decreased expression of RORA impacts the regulation of its target genes in ASD-afflicted individuals (several of which are ASD-relevant genes) and is associated with the pathobiology of ASD, such as with decreases in neuronal differentiation and survival, poorer synaptic transmission and neuroplasticity, diminished cognition and spatial learning, memory impairment, and disrupted development of the cortex and cerebellum [ 36 ].…”

The Clinical Implications of the Academic Performance of the Siblings of Individuals With Autism Spectrum Disorder

“…The etiology of autism spectrum disorder is heterogeneous, and the main contributors are genetic factors and environmental factors [ 17 ]. The precise causal mechanisms remain unclear.…”

“…The precise causal mechanisms remain unclear. Some research studies show that mutated genes in Wnt, sonic hedgehog, and retinoic acid (RA) are related to the etiology of ASD [ 17 ], which backs up the theories of genetic contribution. There is a higher recurrence rate in families with two or more autistic children [ 18 ].…”