Presynaptic, serotonin (5-hydroxytryptamine, 5-HT) transporters (SERTs) limit the signaling potential of 5-HT and recycle 5-HT for further release. SERTs are targets for antidepressants and psychostimulants. Altered SERT expression and function may contribute to multiple neuropsychiatric disorders, including anxiety, OCD, depression and suicide. The majority of studies that explore the contribution of SERT to mental illness have focused on disorders of adult onset. However, increasing evidence demonstrates that 5-HT signaling in the developing brain is critical to establish normal connectivity and behavior and. A key example, autism spectrum disorder (ASD), has been linked to abnormal 5-HT homeostasis for 50 years. The Blakely lab identified and characterized five rare, functional SERT coding variants in ASD subjects, all of which display enhanced 5-HT transport capacity. Blakely's team has developed a transgenic (knock-in) mouse expressing the most common of the ASD SERT variants, Gly56Ala. SERT Ala56 mice display hyperserotonemia and multiple behavioral phenotypes that support the SERT Ala56 model as a powerful platform to understand how compromised 5-HT signaling during development can generate lifelong behavioral deficits. Efforts to capture this opportunity are embraced by Project 3: Modeling the Serotonin Contribution to Autism Spectrum Disorders, In Specific Aim I, Blakely capitalizes on powerful RNA sequencing approaches to elucidate transcriptional networks impacted by SERT Ala56 in raphe neurons, placental tissues and B cells of the immune system.
In Specific Aim II, Blakely seeks to reverse phenotypes associated with SERT Ala56 expression using 5-HT receptor agonists and other molecules suggested from gene network alterations.
In Specific Aim III, Blakely's group develops novel, transgenic mouse models that provides for conditional expression of the SERT 56Ala variant, with the goal of understanding the contribution of specific sites and timing of SERT Ala56 expression to the phenotypes found in mice and humans harboring this variant.
Autism Spectrum Disorder (ASD) is increasingly realized to be much more prevalent than previously believed. Our research focuses on a newly developed animal model carrying an ASD-associated gene variant in the serotonin transporter (SERT), SERT Ala56. SERT is responsible for inactivating serotonin in the brain and periphery and we suspect that altered availability of serotonin contributes to multiple components of ASD.
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