SFARI is pleased to announce that it has awarded 27 grants (21 Pilot Awards and 6 Research Awards) in response to the 2016 Pilot and Research Awards request for applications.
Autism spectrum disorder (ASD) is diagnosed in an increasingly large proportion of the population. Changes in neurocircuitry resulting from alterations in genetic and epigenetic programming are thought to represent an underlying cause of ASD-related behavior, and alterations in the anatomical and electrophysiological properties of local neural circuits in mouse models of ASD have been described. Yet it remains unclear how changes in longer-range neural connectivity are affected in ASD. Bidirectional connections between the thalamus and cortex are one set of long-range projections that are critical for filtering, selecting and perceiving sensory stimuli and generating motor outputs. Interestingly, human imaging studies have implicated thalamocortical circuit dysfunction in ASD.
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.
Autism is a deeply complex and poorly understood developmental brain disorder. Defined genetic disorders that cause autism may be instructive for unraveling the cellular and developmental changes that underlie the disorder.
New genetic variants that increase susceptibility to autism are emerging at a rapid pace. Given the profusion of data, it seems timely to assess the availability and usefulness of mouse models in which to study these genetic risk factors.
Many single-gene disorders linked to autism affect proteins that modulate the translation of messenger RNA into proteins that function at synapses, the junctions between neurons. A few examples are FMRP in fragile X syndrome, TSC1 and TSC2 in tuberous sclerosis complex and PTEN in Cowden syndrome. This led Mark Bear at the Massachusetts Institute of Technology and Raymond Kelleher at Massachusetts General Hospital to propose that ‘troubled translation’ is a core pathophysiological mechanism underlying autism spectrum disorders.