Autism Spectrum Disorder (ASD) is a highly heterogeneous neurodevelopmental disorder characterized by impairments in social communication and restricted, repetitive behaviors, interests, or activities. This disorder is frequently comorbid with other neuropsychiatric disorders, such as attention deficit hyperactivity disorder (ADHD) and anxiety. According to the most recent estimates from the CDC, the prevalence of this disorder is as high as 1 in 68 children and occurs across all socioeconomic, racial, and ethnic groups. This represents a significant clinical, economic, and public health burden. Yet, there are no medications currently available for the treatment of the core symptoms of ASD and its complications. Emerging data implicate dysregulation of dopamine (DA) neurotransmission in conferring susceptibility to ASD and associated neuropsychiatric comorbidities (e.g. anxiety, ADHD). DA neurotransmission is regulated by the dopamine transporter (DAT), which rapidly terminates DA neurotransmission by high-affinity reuptake of released DA into presynaptic terminals. It has been shown that mutations to the human DAT gene (SLC6A3), and specifically a threonine to methionine substitution at position 356 (hDAT T356M), confer risk for ASD and related neuropsychiatric disorders. This de novo mutation has been demonstrated to promote persistent, DAT- mediated reverse transport of DA (here, anomalous dopamine efflux ? ADE). However, it is not yet known whether and how this mutation impacts DA neurotransmission and DA-associated behaviors in mammals. We therefore generated a mouse expressing the DAT T356M variant for use in determining (1) the impact of this mutation on the phenotypic characteristics associated with autism and (2) the dysregulation of DA neurotransmission promoted by ADE in the mammalian brain. We will first explore the impact of this mutation on behaviors known to be regulated, at least in part, by DA neurotransmission and to be altered in individuals with ASD and related disorders (e.g. locomotion, social interactions, repetitive behaviors, anxiety, and changes in interaction with the environment). To determine how the T356M variant affects striatal DA homeostasis and DA dynamics in our newly developed animal model, we will measure DA uptake, DAT surface expression using striatal slice biotinylation, and changes in DA clearance and DA release using ex vivo chronoamperometry and slice amperometry. We will also measure basal extracellular DA using in vivo microdialysis. The proposed studies will provide new insights on how an ASD-associated variant alters DA neurotransmission and how this translates into impairments of specific behaviors. Furthermore, the significance of this proposal is enhanced by the opportunity to define novel molecular mechanisms that confer susceptibility to neuropsychiatric conditions comorbid with ASD, such as ADHD.
Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder affecting 1 in 68 children and represents an estimated economic cost of $268 billion in the US; yet there are few effective therapies available to treat the core symptoms of ASD. The studies contained in this proposal will help us understand the neuronal and behavioral mechanisms by which DA dysregulation promotes aberrant behavior and may represent a novel target for the treatment of the core symptoms of ASD.
