Duplication of a small segment of human chromosome 7 has been found in some children with autism. Lucy Osborne and her colleagues at the University of Toronto aim to understand the effects of duplication of this region, 7q11.23, on the growth and function of the brain. They plan to study this using a mouse model with a similar duplication.
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.
Inflammatory mechanisms have been implicated in autism. Treatments that modulate the immune system and inflammatory response, such as Trichuris suis ova (TSO), a parasitic worm called whipworm helminth, may be an experimental therapeutic option. Individuals with autism may have an increased immune response due to excess type 1 T-helper cells, which increases chronic inflammation. Individuals with autism may also have less of anti-inflammatory cytokines released by type 2 T-helper cells, which decreases chronic inflammation. It has been noted that some individuals with autism have improvements in behavioral symptoms when they have a fever, which further suggests that factors that influence the immune system and inflammation may have a role in autism etiology and potential treatments.
There is growing support for the idea that both genetic and environmental risk factors contribute to autism. One environmental risk is maternal infection, as validated by large epidemiological studies showing links between infection during pregnancy and autism in the child. Similar associations were found with elevated immune responses in maternal serum or amniotic fluid. Also consistent with an immune pathophysiology are findings of activated microglia — immune cells within the brain — in people with autism, as well as dysregulation of immune-related genes in the brain, cerebral spinal fluid and periphery.
Many young children with autism show brain overgrowth soon after birth, suggesting a very early, possibly prenatal origin of autism-linked neuropathological features. Recent findings of substantially increased neuron numbers in the prefrontal cortex of children with autism[ref]Courchesne E. et al. JAMA 306, 2001-2010 (2011) PubMed[/ref] considerably strengthened this notion, as neurogenesis in humans occurs during embryonic and fetal development.
The sense of touch allows us to navigate our physical world. The first step in tactile processing involves the activation of low-threshold mechanoreceptor neurons (LTMRs) with highly specialized endings in the skin. Social (affective) touch may be mediated by a unique class of slowly conducting C-fibers, the C-LTMRs.
Crabtree and Gleeson will focus on rare high-impact genetic mutations for factors in the BAF complex to test how links between neuronal activity and the epigenome may be interrupted in ASD.
Rebecca Saxe will test whether midbrain dopaminergic signals of social cravings, previously observed in mice, are similarly observed in humans. As impairments in social motivation have been postulated to be a core social deficit in autism spectrum disorder (ASD), these results will improve the value of the mouse model for testing mechanisms of altered social motivation in ASD.
Genetic studies of ASD implicate alterations in synaptic development and signaling, with the synaptic protein neurexin-1 playing a pivotal role. Ann Marie Craig aims to develop new approaches to overcome neurexin-1-linked synaptic deficits in ASD by modulating the remaining NRXN1 allele to boost neurexin-1 function and restore synaptic structure and function.
A number of studies have lead to the suggestion that disruptions to chloride homeostasis play a role in a variety of neurological and neurodevelopmental disorders. The neuron-specific potassium chloride co-transporter, KCC2, is the major chloride exporter in neuronal cells, and mutations in SLC12A5 (the gene encoding KCC2) have been reported in individuals with some neurodevelopmental disorders, such as autism spectrum disorder (ASD), epilepsy and schizophrenia. Further, results from KCC2 knockout and knockdown mice highlight the importance of this protein in proper neuronal function.