Individuals with 16p11.2 syndrome, a disorder caused by a deletion or duplication of a section of chromosome 16, exhibit a broad variety of motor abnormalities, including clumsiness, poor coordination, hypotonia (decreased muscle tone) and tremor, as well as some features of autism. The underlying neurobiological basis for motor impairments in 16p11.2 syndrome has not yet been investigated.
Albert Basson and his colleagues at King’s College London plan to study the function of the CHD8 gene in brain development. CHD8, which encodes a protein that changes the structure of chromatin, has emerged as one of the most significant autism-associated genes. In vitro studies — studies conducted in an external environment — have suggested that CHD8 might function as a regulator of the developmentally important WNT signalling pathway, but whether this activity is relevant to CHD8 function during brain development is not known.
The overall goal of Michael Higley’s project was to elucidate the changes in synaptic connectivity caused by interneuron-specific loss of the autism-associated gene tuberous sclerosis complex 1 (TSC1). Higley and his group used electrophysiological analyses to reveal that deletion of TSC1 from a subclass of GABAergic interneurons that express the marker parvalbumin produces an increase in synaptic inhibition onto nearby excitatory pyramidal neurons. This result is surprising, as previous studies found that global deletion of TSC1 resulted in weakened inhibition and hyperexcitability in the network[ref]Bateup H.S. et al. Neuron 78, 510-522 (2013) PubMed[/ref],[ref]Bateup H.S. et al. J. Neurosci. 31, 8862-8869 (2011) PubMed[/ref]. Higley’s findings illustrate that dysfunction of autism-linked genes can produce complex and competing outcomes depending on the identity of neurons affected.
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.
Autism spectrum disorders are genetically heterogeneous, but whether they share a common neural circuit-processing defect is unclear. One emerging hypothesis is that the ratio of excitation to inhibition in the brain's cerebral cortex is elevated in people with the autism, leading to hyperexcitability of neural circuits, impaired information processing, increased seizure risk and hypersensitivity to sensory stimuli.
Studies since 2010 have identified a large number of genes that, when mutated, cause autism. One can group the products of these mutated genes into two categories: proteins located at the synapses, or functional connections between nerve cells, and proteins located in the cell nucleus.
Clinical studies in 2011 showed a completely novel genetic link between the VIPR2 gene and both schizophrenia and autism. In addition to providing a new clue to the pathophysiology of these mental health disorders, this finding is particularly exciting because the implicated gene encodes a cell surface neuropeptide receptor — a type of molecule that is generally targetable with drugs.
KATNAL2 is a recently identified autism gene that is predicted to code for a microtubule-severing enzyme. However, researchers don’t know how this gene is involved in brain development or what cellular events in the developing brain go awry if it is mutated. Xiaobing Yuan and Peter Baas are studying whether KATNAL2 and other autism genes play an essential role in neuronal migration through the regulation of microtubule dynamics.
The way a child with autism communicates through speech plays a significant role in educational, psychosocial and eventual vocational aspects of quality of life. Some children with autism, both with and without language impairment, have challenges acquiring articulate speech and mastering the prosodic features expected when speaking in different situations.
Accumulating evidence suggests that autism spectrum disorder symptoms arise from a disruption in the process of experience-dependent synaptic plasticity that normally occurs during critical periods of development. Critical periods are windows of time when appropriate sensory, motor and cognitive function are essential for the refinement and tuning up of brain circuits. Rett syndrome is recognized as one of the clearest genetic examples of autism, and is caused by mutations in the MeCP2 gene.