Alterations in serotonin (5-hydroxytryptamine, 5-HT) neurotransmission have long been theorized to play an important role in the pathogenesis of psychiatric disorders, particularly depression. This theory stems from the facts that drugs (e.g., SSRIs) increasing levels of extracellular 5-HT (5-HTExt) treat depression with moderate efficacy and that anomalies in putative """"""""biomarkers"""""""" of central 5-HT function have been repeatedly reported in depression. However, brain 5-HT dysfunction has never been directly demonstrated in depression patients and whether low 5-HT can elicit or predispose to depression remains unclear. The rate-limiting step in brain 5-HT synthesis is the conversion of tryptophan to 5-hydroxytryptophan (5-HTP) by tryptophan hydroxylase 2 (Tph2). The recent identification of functional mutations in several of the genes involved in 5-HT homeostasis, including tph2, and their associations with depression or impaired therapeutic responses to SSRIs have stimulated renewed interest in the 5-HT deficiency theory of depression. We have generated a mouse line carrying a rare Tph2(R439H) mutation originally identified in a depression cohort. In these mutant mice brain 5- HT synthesis and tissue storage are decreased by 80% and 5-HTExt levels by 60-80%, while evoked 5-HTExt responses are qualitatively preserved. The mice recapitulate several anomalies in putative 5-HT biomarkers reported in severe depression and exhibit depression-, anxiety-, and aggressive-like behaviors, seemingly providing a model of the behavioral alterations associated with 5-HT deficits in humans. Thus, our mutant (henceforth 5-HThypo) mice may represent a unique naturalistic model of 5-HT deficiency and, possibly, depression. Plausibly, multiple diverse insults to 5-HT homeostasis could each result in 5-HT deficiency, thus the 5-HThypo mouse likely represents a useful model of 5-HT deficiency in general as well as a model of impaired Tph2 catalytic function. The overall goal of our continued research is to use the 5-HThypo mouse to better understand how 5-HT deficiency contributes to depression etiology and affects antidepressant treatment, including the consequences for stress susceptibility and responses to current and novel therapies. For this goal, we propose four specific aims.
Aim 1 will define whether 5-HT deficiency alters susceptibility to stress, as tested in the social defeat and chronic mild stress paradigms.
Aim 2 will test whether antidepressant- like responses to SSRI and ketamine are affected by 5-HT deficiency.
Aim 3 will pre-clinically test a novel 5- HTP-based antidepressant augmentation concept under 5-HT-deficient and normal conditions.
In Aim 4 we will use conventional and state-of-the-art approaches to identify the cellular signaling pathway changes underlying the depression-like behaviors arising consequent to 5-HT deficiency. Collectively, the proposed experiments will address long outstanding questions in depression neurobiology and test a new treatment concept.

Public Health Relevance

For more than 5 decades, deficiencies in the 5-HT system have been proposed to play important roles in several affective disorders, notably depression. Direct evidence for this hypothesis, however, is lacking. We have developed a genetically engineered humanized mouse model with a marked reduction in brain 5-HT synthesis and neurotransmission that represents a unique naturalistic model of 5-HT deficiency. Determining the biochemical, cellular, and behavioral consequences of brain 5-HT deficiency in these mice will provide unique insights into the neuronal mechanisms underlying impaired mood regulation and should provide a foundation for identifying novel targets and developing new concepts for improved therapies.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
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Special Emphasis Panel (ZRG1-MDCN-N (04))
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Winsky, Lois M
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Duke University
Anatomy/Cell Biology
Schools of Medicine
United States
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Hultman, Rainbo; Ulrich, Kyle; Sachs, Benjamin D et al. (2018) Brain-wide Electrical Spatiotemporal Dynamics Encode Depression Vulnerability. Cell 173:166-180.e14
Sachs, Benjamin D; Tran, Ha L; Folse, Emily et al. (2018) Brain-region-specific Molecular Responses to Maternal Separation and Social Defeat Stress in Mice. Neuroscience 373:122-136
Jacobsen, Jacob Pr; Rudder, Meghan L; Roberts, Wendy et al. (2016) SSRI Augmentation by 5-Hydroxytryptophan Slow Release: Mouse Pharmacodynamic Proof of Concept. Neuropsychopharmacology 41:2324-34
Jacobsen, Jacob P R; Krystal, Andrew D; Krishnan, K Ranga R et al. (2016) Adjunctive 5-Hydroxytryptophan Slow-Release for Treatment-Resistant Depression: Clinical and Preclinical Rationale. Trends Pharmacol Sci 37:933-944
Sachs, Benjamin D; Ni, Jason R; Caron, Marc G (2015) Brain 5-HT deficiency increases stress vulnerability and impairs antidepressant responses following psychosocial stress. Proc Natl Acad Sci U S A 112:2557-62
Cheng, Y; Rodriguiz, R M; Murthy, S R K et al. (2015) Neurotrophic factor-?1 prevents stress-induced depression through enhancement of neurogenesis and is activated by rosiglitazone. Mol Psychiatry 20:744-54
Sachs, Benjamin D; Rodriguiz, Ramona M; Tran, Ha L et al. (2015) Serotonin deficiency alters susceptibility to the long-term consequences of adverse early life experience. Psychoneuroendocrinology 53:69-81
Sachs, Benjamin D; Salahi, A Ayten; Caron, Marc G (2014) Congenital brain serotonin deficiency leads to reduced ethanol sensitivity and increased ethanol consumption in mice. Neuropharmacology 77:177-84
Sachs, Benjamin D; Caron, Marc G (2014) Chronic fluoxetine increases extra-hippocampal neurogenesis in adult mice. Int J Neuropsychopharmacol 18:
Jacobsen, Jacob P R; Plenge, Per; Sachs, Benjamin D et al. (2014) The interaction of escitalopram and R-citalopram at the human serotonin transporter investigated in the mouse. Psychopharmacology (Berl) 231:4527-40

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