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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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; Ni, Jason R; Caron, Marc G (2014) Sex differences in response to chronic mild stress and congenital serotonin deficiency. Psychoneuroendocrinology 40:123-9
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
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
Sachs, B D; Jacobsen, J P R; Thomas, T L et al. (2013) The effects of congenital brain serotonin deficiency on responses to chronic fluoxetine. Transl Psychiatry 3:e291
Sachs, Benjamin D; Rodriguiz, Ramona M; Siesser, William B et al. (2013) The effects of brain serotonin deficiency on behavioural disinhibition and anxiety-like behaviour following mild early life stress. Int J Neuropsychopharmacol 16:2081-94
Hara, Makoto R; Sachs, Benjamin D; Caron, Marc G et al. (2013) Pharmacological blockade of a *(2)AR-*-arrestin-1 signaling cascade prevents the accumulation of DNA damage in a behavioral stress model. Cell Cycle 12:219-24
Siesser, William B; Sachs, Benjamin D; Ramsey, Amy J et al. (2013) Chronic SSRI treatment exacerbates serotonin deficiency in humanized Tph2 mutant mice. ACS Chem Neurosci 4:84-8
Jorgensen, Christinna V; Jacobsen, Jacob P; Caron, Marc G et al. (2013) Cerebral 5-HT2A receptor binding, but not mGluR2, is increased in tryptophan hydroxylase 2 decrease-of-function mice. Neurosci Lett 555:118-22
Dzirasa, Kafui; Kumar, Sunil; Sachs, Benjamin D et al. (2013) Cortical-amygdalar circuit dysfunction in a genetic mouse model of serotonin deficiency. J Neurosci 33:4505-13

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