It is well established that homeostatic signaling systems interface with the mechanisms of developmental and learning-related plasticity to achieve stable yet flexible neural function and animal behavior. Experimental evidence from organisms as diverse as Drosophila, mice and humans demonstrates that homeostatic signaling systems stabilize neural function through the modulation of synaptic transmission, ion channel abundance and neurotransmitter receptor trafficking. At a fundamental level, if homeostatic plasticity is compromised, then the nervous system will be less robust to perturbation. As such, it is widely speculated that defective or maladaptive homeostatic plasticity will be relevant to the cause or severity of autism. However, clear molecular or genetic links between autism and homeostatic plasticity have yet to be defined in any organism.

Between 55 and 70 percent of children with autism spectrum disorders (ASDs) experience sensory over-responsivity (SOR), a severe and negative response to, or avoidance of, sensory stimuli such as noisy environments, unexpected loud noises, scratchy clothing or being touched. Children with ASD and SOR have more anxiety, greater functional impairment and poorer social outcomes than those without it. Because SOR has only recently been considered in the diagnostic criteria for ASD, it has not yet been well studied and little is known about brain mechanisms of SOR or how to treat it.

Recent studies have provided compelling evidence that loss-of-function mutations in the CHD8 gene, which encodes an ATP-dependent chromatin-remodeling factor, are associated with an autism subtype characterized by macrocephaly, specific craniofacial features and gut immobility. The CHD8 protein modifies the structure of chromatin in the cell nucleus, and in vitro studies have suggested that CHD8 might function as a regulator of the developmentally important Wnt and PTEN signaling pathways. Tight control of both of these pathways is critical for normal brain development, and mutations that affect their activity have been strongly associated with autism and brain size. It is therefore important to test whether CHD8 functions as a regulator of these pathways during brain development.

Autism spectrum disorders (ASDs) and related neuropsychiatric diseases, such as schizophrenia, are thought to involve alterations in neural circuitry in different brain regions, including the hippocampus, an area critical for memory formation. Most studies on the role of the hippocampus in learning and memory have focused on information flow through the hippocampal CA3, CA1 and dentate gyrus subregions. Much less is known about the hippocampal CA2 region, a relatively small area that is altered in individuals with schizophrenia and bipolar disorder. The CA2 region is of particular interest in ASD because it has high levels of receptors for the social hormones oxytocin and vasopressin, which have been implicated in ASD.

Medications for treating the core symptoms of autism spectrum disorder (ASD) continue to be an unmet need. The only medications approved by the U.S. Food and Drug Administration (FDA) for the treatment of individuals with ASD are effective in treating irritability and associated aggressive behaviors, but these medications can also cause severe long-term side effects such as diabetes and involuntary motor movements. Effective medications with more tolerable side effect profiles are highly desirable.

Despite the existence of a core set of features and affected biological networks, autism spectrum disorders (ASDs) are genetically heterogeneous. While variants in hundreds of genes have been implicated as causal or risk-conferring for ASD, a large percentage of the heritability of ASDs remains unaccounted for. This suggests that a number of inherited causal or risk mutations linked to autism have gone undiagnosed.

Many of the social and cognitive behavioral impairments associated with autism spectrum disorders (ASDs) are likely caused by changes in early brain development that alter the formation of neural circuits, and in particular, the neural circuitry of the cerebral cortex. Because early brain development is completed long before the onset of any identifiable behavioral changes, most studies of the developmental origins of autism have focused on animal models of genetic syndromes or rare single-gene mutations that lead to ASD-like behaviors. It is not clear how these different syndromes may be related to one another, or how these distinct genetic changes can each lead to similar behavioral outcomes.

Atypical sensory processing is a proposed etiological factor underlying the development of behavioral deficits in autism spectrum disorder (ASD). In particular, hypo-responsiveness to sensory social stimuli reduces social orienting, thus limiting the number of opportunities in which social learning can occur. Indeed, poorer social communication skills in individuals with ASD are associated with hypo-responsiveness to multiple sensory modalities.

One of the most critical challenges in the identification of new medications to treat autism spectrum disorders (ASDs) is our limited understanding of the biological mechanisms underlying these disorders. In recent years, there have been considerable advances in the genetics of ASD, with a resulting rapidly accumulating pool of reliable ASD risk genes. Currently, we need systems that will allow us to progress from gene discovery to the illumination of relevant biological pathways and novel therapeutics.