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.
|Bermingham, Daniel P; Blakely, Randy D (2016) Kinase-dependent Regulation of Monoamine Neurotransmitter Transporters. Pharmacol Rev 68:888-953|
|Zhang, Zhaiyi; Shen, Manli; Gresch, Paul J et al. (2016) Oligonucleotide-induced alternative splicing of serotonin 2C receptor reduces food intake. EMBO Mol Med 8:878-94|
|Wyler, Steven C; Spencer, W Clay; Green, Noah H et al. (2016) Pet-1 Switches Transcriptional Targets Postnatally to Regulate Maturation of Serotonin Neuron Excitability. J Neurosci 36:1758-74|
|Whitney, Meredith Sorenson; Shemery, Ashley M; Yaw, Alexandra M et al. (2016) Adult Brain Serotonin Deficiency Causes Hyperactivity, Circadian Disruption, and Elimination of Siestas. J Neurosci 36:9828-42|
|Robson, Matthew J; Zhu, Chong-Bin; Quinlan, Meagan A et al. (2016) Generation and Characterization of Mice Expressing a Conditional Allele of the Interleukin-1 Receptor Type 1. PLoS One 11:e0150068|
|Margolis, Kara Gross; Li, Zhishan; Stevanovic, Korey et al. (2016) Serotonin transporter variant drives preventable gastrointestinal abnormalities in development and function. J Clin Invest 126:2221-35|
|Brindley, Rebecca L; Bauer, Mary Beth; Blakely, Randy D et al. (2016) An interplay between the serotonin transporter (SERT) and 5-HT receptors controls stimulus-secretion coupling in sympathoadrenal chromaffin cells. Neuropharmacology 110:438-48|
|Wu, Hsiao-Huei; Choi, Sera; Levitt, Pat (2016) Differential patterning of genes involved in serotonin metabolism and transport in extra-embryonic tissues of the mouse. Placenta 42:74-83|
|Goeden, Nick; Velasquez, Juan; Arnold, Kathryn A et al. (2016) Maternal Inflammation Disrupts Fetal Neurodevelopment via Increased Placental Output of Serotonin to the Fetal Brain. J Neurosci 36:6041-9|
|Ellegood, J; Anagnostou, E; Babineau, B A et al. (2015) Clustering autism: using neuroanatomical differences in 26 mouse models to gain insight into the heterogeneity. Mol Psychiatry 20:118-25|
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