Edited by: Raina Robeva, Randolph-Macon College and Sweet Briar College, USA
Reviewed by: Gabriel Dichter, University of North Carolina at Chapel Hill, USA
*Correspondence: Gül Dölen
This article was submitted to Systems Biology, a section of the journal Frontiers in Neuroscience
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Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by impairments in social communication skills, as well as stereotyped movements and restricted interests (DSM-5; American Psychiatric Association,
Although, deficits in social interactions and restrictive, repetitive patterns of behavioral output are seemingly unrelated symptom domains, growing appreciation of striatal function suggests that this brain region regulates behavioral flexibility, motivational state, goal-directed learning, and attention. The review articles by
Circuit-level explanations of ASD pathogenesis are appealing because they most directly account for the emergence of clinical symptoms; however, because ASD genes are expressed across the whole brain, it is at this time unclear how specific circuits, cell types and brain regions are more likely to be involved in producing symptoms. One compelling possibility is that this pattern emerges through pathoclisis (i.e., the whole brain is exposed to the insult, in this case genetic lesion, but certain subtypes of cells, localized to distinct brain regions or circuits, are more susceptible to injury). Alternatively, the selective involvement of certain brain regions or circuits may reflect the case that these circuits are recruited as a compensatory shunting mechanism for symptoms that arise in a distributed fashion throughout multiple brain regions and circuits (this alternative is perhaps analogous to “abdominal guarding” whereby the muscles of the abdominal wall contract when there is injury to any of the organs found within the abdominal cavity). In the case of pathoclisis, future studies aimed at understanding how certain cell types become selectively susceptible may yield important pathogenic mechanisms and therapeutic targets. In the case of compensatory shunting, examining underlying, and unifying biochemical or molecular mechanisms will be critical for understanding the pathogenesis.
The first suggestion that ASD might be thought of as a “synaptopathy” was driven by the observation that the dozen or so ASD risk genes known at the time, all encode synaptic proteins, and could be linked together by biochemical signaling pathways that regulate synaptic pruning and plasticity during early post-natal development. Later, the Fragile X mental retardation protein (FMRP), which is absent in patients with Fragile X (the first identified and most common cause of ASD) binds to nearly one quarter of identified ASD candidate genes, suggesting that this protein might serve as a central node for ASD pathogenesis. Interestingly, even as we discover novel unifying mechanisms, these early speculations are also being borne out by genetic pathway analysis. Several reviews in this volume address these unifying mechanisms revealed by molecular, biochemical, and genetic pathway analysis.
We are currently at a critical juncture in ASD research. As we discover more and more pathogenic mechanisms, it is important to step back and synthesize so that we may generate novel testable hypothesis about whether and how these mechanisms may intersect to produce the common symptoms of ASD. We hope that the papers brought together in this Frontiers Research Topic will serve to stimulate that conversation and provide the readers with new ideas and perspectives toward such convergent mechanisms and circuits.
All authors listed, have made substantial, direct, and intellectual contribution to the work, and approved it for publication.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
GD is funded by the Searle Scholars Program (Kinship Foundation) and the Hartwell Individual research award (Hartwell Foundation). MS is funded by the National Institutes of Health (NIH) (U01NS082320, P20NS080199, P30HD018655) and the Rare Diseases Clinical Research Network (RDCRN; U54NS092090). RDCRN is an initiative of the Office of Rare Diseases Research (ORDR), National Center for Advancing Translational Sciences (NCATS), funded through collaboration between NCATS, NINDS, NICHD, and NIMH.