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.

Public Health Relevance

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.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Specialized Center (P50)
Project #
Application #
Study Section
Special Emphasis Panel (ZMH1)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Vanderbilt University Medical Center
United States
Zip Code
Spencer, William C; Deneris, Evan S (2017) Regulatory Mechanisms Controlling Maturation of Serotonin Neuron Identity and Function. Front Cell Neurosci 11:215
Knoll, A T; Jiang, K; Levitt, P (2017) Quantitative trait locus mapping and analysis of heritable variation in affiliative social behavior and co-occurring traits. Genes Brain Behav :
Ritter, K Elaine; Wang, Zunyi; Vezina, Chad M et al. (2017) Serotonin Receptor 5-HT3A Affects Development of Bladder Innervation and Urinary Bladder Function. Front Neurosci 11:690
O'Neil, Richard T; Wang, Xiaojing; Morabito, Michael V et al. (2017) Comparative analysis of A-to-I editing in human and non-human primate brains reveals conserved patterns and context-dependent regulation of RNA editing. Mol Brain 10:11
Sharif, N F; Korade, Z; Porter, N A et al. (2017) Oxidative stress, serotonergic changes and decreased ultrasonic vocalizations in a mouse model of Smith-Lemli-Opitz syndrome. Genes Brain Behav 16:619-626
Siemann, J K; Muller, C L; Forsberg, C G et al. (2017) An autism-associated serotonin transporter variant disrupts multisensory processing. Transl Psychiatry 7:e1067
Brindley, Rebecca L; Bauer, Mary Beth; Blakely, Randy D et al. (2017) Serotonin and Serotonin Transporters in the Adrenal Medulla: A Potential Hub for Modulation of the Sympathetic Stress Response. ACS Chem Neurosci 8:943-954
Simmler, Linda D; Anacker, Allison M J; Levin, Michael H et al. (2017) Blockade of the 5-HT transporter contributes to the behavioural, neuronal and molecular effects of cocaine. Br J Pharmacol 174:2716-2738
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
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 110:438-448

Showing the most recent 10 out of 41 publications