Autism spectrum disorder (ASD) affects as many as 1 in 150 children. It is a complex developmental disorder characterized by social deficits, language impairment, and restricted interests (Newschaffer et al., 2007;Levitt and Campbell, 2009). Genetic linkage techniques recently revealed that individuals with ASD are three times more likely to have a mutation in the promoter region of the gene for MET receptor tyrosine kinase (hereafter MET), which results in reduced MET expression (Campbel et al., 2006;Campbel et al., 2007). The MET signaling pathway is important for the normal development of the cerebral cortex (Powell et al., 2001;Powell et al., 2003;Levitt et al., 2004;Gutierrez et al., 2004). Interference with this pathway affects cortical development in a number of ways. Still unknown however, is the extent to which the functional organization of cortical circuits is affected by MET dysfunction. Of particular interest to ASD research is the synaptic organization of the frontal cortex, which is involved in many higher order cognitive aspects of behavior and executive functioning. Evidence suggests long-range under-connectivity between cortical areas in ASD (Horwitz et al., 198;Courchesne and Pierce, 2005;Kana et al., 2007). From this view, ASD is a disorder of cortical circuits. It has been proposed that there is also an over-strengthening of local connectivity in ASD (Courchesne and Pierce, 2005), but this has yet to be directly measured. The availability of a MET- knockout (MET-KO) mouse will allow me to measure changes in synaptic connectivity that result from interference with the MET signaling pathway. I hypothesize that local synaptic connections in frontal cortex are over-strengthened as a result of MET- KO. I will test this hypothesis by measuring the circuit abnormalities of corticostriatal neurons with high throughput circuit mapping techniques (Weiler et al., 2008;Yu et al., 2008;Wood et al., 2009, Anderson 2010). I will focus on corticostriatal neurons because these neurons provide long-range input to other cortical areas (Wilson, 1987;Reiner et al., 2003) and the projection is a key component in loops linking the frontal cortex with the basal ganglia and the thalamus important for the selection and initiation of behavior (Albin et al., 1989). Understanding altered cortical connectivity in MET-KO will be an important step towards characterizing the nature of cortical circuit disorders associated with ASD. It will provide a basis for understanding the mechanisms underlying the changes to the brain in ASD.
As many 1 in 150 children are diagnosed with autism spectrum disorder (ASD), which is a complex developmental disorder characterized by abnormal social interactions, language deficits, and restricted interests. Evidence implicates alterations to the circuits of the frontal cortex in ASD, but to date, no detailed, cell-level resolution of synaptic connectivity in non-syndromic ASD has been obtained. We will characterize the cortical circuits of a mouse model of cortical circuit dysfunction in ASD, which will yield important insight into the mechanism underlying differences in the synaptic organization of the frontal cortex, and help understand the changes that occur in the brains of people with ASD.
| Srivastava, Deepak P; Woolfrey, Kevin M; Jones, Kelly A et al. (2012) An autism-associated variant of Epac2 reveals a role for Ras/Epac2 signaling in controlling basal dendrite maintenance in mice. PLoS Biol 10:e1001350 |
