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.
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.
Carlos Portera-Cailliau plans to investigate how brain circuits are altered in animal models of autism and intellectual disability. Portera-Cailliau and his colleagues at the University of California, Los Angeles (UCLA) aim to use state-of-the-art microscopy techniques to study brain areas that, in experimental models of autism, are important for emotion, cognition, creativity, learning and memory. The group’s experiments are designed to provide insight into how subtle alterations in brain wiring and connectivity can result in neuropsychiatric disorders such as autism.
André Fenton and his group at New York University hypothesize that a common pathophysiology underlies the failures of cognitive flexibility that are characteristic of autism. Fenton aims to investigate the widely held ‘discoordination’ hypothesis that in individuals with autism, the neural computations within and between networks of cells that depend upon precisely coordinated neural activity are impaired.
Learning to automatize actions and form habits is critical for mastering everyday skills and activities such as riding a bike, speaking or writing. However, having overly automatized actions can lead to an overabundance of stereotyped, repetitive behaviors and to lack of control or ability to switch between habits and novel behavioral patterns.
Numerous genetic pathways have been implicated in autism, and the effects on neural function of genetic variations in these pathways have been studied. However, it has been difficult to identify how these pathways converge to a common level of neural function. It remains unclear how similarities in autism across patients with different genetic variations occurs.
Significant progress has been made on identifying and characterizing the molecular and genetic changes that contribute to the altered patterns of brain development and connectivity in autism. We do not yet understand how these cellular changes alter brain circuits or how changes in those circuits cause the behavioral manifestations of autism.
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.