Chromosomal copy number variations (CNVs) are common genetic abnormalities in autism spectrum disorder (ASD) and have been identified in approximately 10 percent of individuals with ASD. Currently, there is a knowledge gap in the understanding of the molecular and synaptic mechanisms underlying CNV-associated ASD.
Autism spectrum disorders (ASDs) comprise a constellation of symptoms, including impaired social interactions, communication and language deficits, and repetitive behaviors that manifest during early development. Various genetic targets associated with ASDs have been identified, but given the spectrum of symptoms, it has become clear that multiple genes play a part in the disorder. Dysfunction of cortical connectivity is thought to be a hallmark of ASDs, and many of the genes implicated in ASD are involved in synapse formation and function. Although many recent studies have investigated synaptic connections in ASD, the underlying mechanisms are still unknown.
In a previously funded SFARI study of 100 children with autism spectrum disorder (ASD), Ruth O’Hara and her colleagues found that sleep-disordered breathing (SDB) — such as sleep apnea — occurs in more than 40 percent of children with ASD, a far higher rate than that seen in typically developing children. SDB is strongly linked to cognitive and behavioral deficits and elicits a systemic inflammatory response. Recent studies have focused on the role of microparticles (MPs) in SDB disorders. Cell-derived MPs are microvesicles of 0.05 to 1 micrometers, released through exocytic budding of the plasma membrane, following stimulation of different cell types.
How children recognize emotion from facial expressions, understand others’ perspectives, reason through social problems and regulate emotion is critical to their social success. These social cognition skill areas are often affected in children with autism spectrum disorders (ASDs). They are also frequent targets of both behavioral and medical interventions for ASD. There are no reliable, comprehensive, easy-to-use, scalable and standardized assessment tools available to measure responsiveness to treatment in each of these social domains among children with ASD.
Williams syndrome (WS) is a neurodevelopmental disorder caused by deletions in the 7q11.23 chromosomal region. Individuals with WS show developmental delays, learning disabilities and excessively social behavior. Interestingly, individuals with duplications of this same chromosomal region display a symmetrically opposite phenotype with regard to social behavior. This genomic segment therefore offers a unique opportunity to understand the molecular underpinnings of social behaviors.
Compelling evidence suggests that the 15q11-13 chromosomal region is likely to play a role in autism pathogenesis. Mutations of the UBE3A gene, which is located in this region, cause Angelman syndrome (AS), a neurodevelopmental disorder that has strong phenotypic overlap with autism. UBE3A is an E3 ubiquitin ligase and has been shown to be an important regulator of protein homeostasis and synapse development and plasticity. Separately, there is growing evidence that neuronal autophagy plays a role in supporting proper morphological development and synaptic connectivity refinement.
Pupillometry, the measurement of pupil diameter, provides a glimpse into the internal mechanisms that guide attention and focused states. Among a number of innervations within the cortex, locus coeruleus-norephinephrine (LC-NE) connections modulate brain regions involved in visual attention, and pupil response serves as a biomarker for activation within the LC-NE system. Due to its degree of influence, small mechanistic differences in LC-NE functioning may lead to cascading deficits across various neurological domains. Aberrant pupil/LC-NE response has been demonstrated in a variety of clinical populations, including individuals with autism spectrum disorder (ASD), in whom hyperphasic activity has been found to facilitate enhanced visual perception in visual search tasks[ref]Blaser E. et al. Sci. Rep. 4, 4301 (2014) PubMed[/ref]. While hyperfocused attention may be specific to ASD, repetitive behaviors and restricted interests (RBRI) are frequently observed in a variety of developmental brain disorders, as well as in typical development, and may be best described as a dimensional construct.
The generation of all-or-none action potentials is critical for proper brain function. At the heart of action potential generation are voltage-gated sodium channels, which underlie the rising, or depolarizing, phase of the action potential. Twelve different mutations in the SCN2A gene, which encodes the neuronal sodium channel NaV1.2, have been identified in two large autism genetic studies.
Abnormal patterns of head and brain growth have been reported in a subset of individuals with autism. A heterogeneous collection of genetic risk factors for autism and micro- and macrocephaly have been identified, including mutations in genes acting in the PI3K-AKT-mTOR (e.g., PTEN) and Wnt-beta-catenin (e.g., CTNNB1, CHD8 and TCF4) signaling pathways.
Opioids have long been implicated in social behaviors. Reducing opioid activity increases affiliative social behaviors and social reward-seeking while lowering stereotypies and self-injurious behaviors. The specific role of opioid blockers in complex social cognition, however, requires more investigation.