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.
Barry Connors and Brian Theyel propose to understand how the thalamocortical circuitry is modified in two mouse models – TSC1 and NHE6. TSC1 is a known ASD risk gene, whereas mutations in NHE6 (also known as SLC9A6) cause the neurodevelopmental disorder Christianson syndrome, a disorder that shares some of the core features of ASD. Misregulation of NHE6 has also been reported in the ASD brain1. Both genes play critical roles in axonal arborization during neurodevelopment, yet the functions, and functional alterations, of forebrain circuits in these models remain unclear.
The researchers plan to use a previously developed TSC1 mouse model that lacks TSC1 specifically in thalamocortical relay cells while still recapitulating ASD-related behaviors2. Whole-brain visualization of thalamocortical axons will be performed and fine-scale anatomical and physiological changes within the thalamocortical neural pathway will be assessed. The researchers will then compare alterations in the TSC1 mouse model to alterations in an NHE6 mouse model3, which has yet to have its thalamocortical circuitry analyzed. As mutations in TSC1 and NHE6 lead to brain abnormalities by very different molecular mechanisms, this approach will allow Connors and Theyel to determine whether there are any core long-range circuit dysfunctions linked to ASD-related behaviors. Identification of such core circuitry would provide potential insight into treatments targeting ASD-related changes in neural activity, helping researchers to further understand and potentially treat autism.