Identifying Essential Cell Types and Circuits in Autism Spectrum Disorders

Abstract

Autism spectrum disorder (ASD) is highly genetic in its etiology, with potentially hundreds of genes contributing to risk. Despite this heterogeneity, these disparate genetic lesions may result in the disruption of a limited number of key cell types or circuits –information which could be leveraged for the design of therapeutic interventions. While hypotheses for cellular disruptions can be identified by postmortem anatomical analysis and expression studies of ASD risk genes, testing these hypotheses requires the use of animal models. In this review, we explore the existing evidence supporting the contribution of different cell types to ASD, specifically focusing on rodent studies disrupting serotonergic, GABAergic, cerebellar and striatal cell types, with particular attention to studies of the sufficiency of specific cellular disruptions to generate ASD-related behavioral abnormalities. This evidence suggests multiple cellular routes can create features of the disorder, though it is currently unclear if these cell types converge on a final common circuit. We hope that in the future, systematic studies of cellular sufficiency and genetic interaction will help to classify patients into groups by type of cellular disruptions which suggest tractable therapeutic targets.

The RNA-binding protein Celf6 is highly expressed in diencephalic nuclei and neuromodulatory cell populations of the mouse brain

“…The neurocircuitry disrupted in ASD remains an important unknown of this disorder, however, there are brain regions and cell types implicated in the different symptom domains (Maloney et al 2013). Communication deficits are tightly coupled with the social disruptions at the core of ASD, but distinct regions are thought to play a role in communication.…”

“…This argues against the Celf6 −/− phenotype being primarily a result of motoric deficits, and suggests there may be some upstream motivational deficit, despite a loss of the protein in the Amb. Disruption in the function of the dorsal striatum, a structure associated with behavioral motivation across species, has been suggested to underlie the repetitive interests and resistance to change behavior patterns observed in ASD patients (Maloney et al 2013; Sears et al 1999). Celf6 protein was not highly expressed in the output neurons of this region (the medium spiny neurons that make of the large proportion of the cells here); however, there was robust expression in both the striatal cholinergic interneurons and the dopaminergic inputs to this structure.…”

“…It is possible that the absence of Celf6 in the raphe, VTA or LC is also impacting behavioral performance of the mice due to the far-reaching influence these cell populations have on overall brain function (Maloney et al 2013). The serotonergic system, for example, has been implicated in the etiology of a subset of ASD cases.…”

FoxP1 orchestration of ASD-relevant signaling pathways in the striatum

“…1A). Three brain regions relevant to ASD with substantial levels of Foxp1 expression are the striatum, hippocampus, and neocortex (Ferland et al 2003;Maloney et al 2013). We quantitatively determined an ∼50% reduction in total Foxp1 protein levels (isoforms A and D) in the Foxp1 +/− hippocampus or striatum compared with control littermates (Fig.…”

Assessment of Biometal Profile in Children with Autism Spectrum Disorder, with Attention Deficit Hyperactivity Disorder, or with Other Psychiatric Diagnoses: A Comparative Outpatient Study

“…Striatal dopamine innervation plays a role in striatal plasticity [60]. Alterations in striatal dopamine levels lead to disorders that can have both motor and cognitive dysfunction such as ASD [61] and ADHD [62].…”