The brain serotonin (5HT) system plays a critical role in numerous neuronal functions and dysregulation of its homeostasis contributes to many psychiatric disorders. Numerous conditions such as major depression, obsessive compulsive disorder, anxiety and panic disorder, are effectively treated by raising the extracellular concentrations of brain 5HT using selective serotonin re-uptake inhibitors (SSRI). Tryptophan hydroxylase (TPH2) the rate-limiting enzyme for the synthesis of 5HT is expressed selectively in neurons while TPH1 is expressed peripherally. There is a high degree of sequence conservation between TPH1 and TPH2 and other mono-oxygenases for tyrosine (TH) and phenylalanine (PAH). We initially identified a single nucleotide polymorphism (SNP) in the mouse Tph2 gene that results in a ~ 50% decrease in the in vitro activity of the enzyme that correlates with a similar reduction in brain 5HT synthesis and content in inbred mice carrying the SNP. A similar mutation in the human TPH2 (R441H) was then identified in a cohort of elderly unipolar depressed patients, which decreased the activity of the enzyme by >80% and was associated with reduced responsiveness to therapeutic effects of SSRI in the patients. A mutation at the exact same codon in PAH represents the most severe and prevalent mutation in phenylketonuria where more than 300 coding mutations have been identified. Several additional SNPs in the coding regions of human TPH2 have recently been identified but not yet characterized. We have developed a knockin mouse carrying a (R439H) mutation in mTph2, equivalent to the (R441H) mutation in humans. We are also generating congenic mouse lines carrying the functional (C1473G) SNP in mTph2 in both C57BI/6J and BALB/cJ backgrounds. The overall goal of this proposal is to determine the neurochemical and behavioral consequences of this mutation and establish the biological significance of such mutations in the human TPH2 gene. There are three Specific Aims: 1) Neurochemical and behavioral characterization of Tph2(R439H) knockin and congenic mouse lines;2) Sequence anlysis of TPH2 in different cohorts of 5-HT-related neuropsychiatric conditions and 3) Characterization of novel functional human TPH2 mutants in cellular systems and genetically modified animals. Results from these experiments should provide potential genetic determinants for 5-HT-related disorders as well as useful animal models to explore the actions of and responsiveness to SSRI and test new therapeutic approaches.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH079201-05
Application #
7993059
Study Section
Molecular Neuropharmacology and Signaling Study Section (MNPS)
Program Officer
Beckel-Mitchener, Andrea C
Project Start
2006-12-15
Project End
2012-05-31
Budget Start
2010-12-01
Budget End
2012-05-31
Support Year
5
Fiscal Year
2011
Total Cost
$334,491
Indirect Cost
Name
Duke University
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
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
Cheng, Y; Rodriguiz, R M; Murthy, S R K et al. (2015) Neurotrophic factor-α1 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 (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
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; Caron, Marc G (2014) Chronic fluoxetine increases extra-hippocampal neurogenesis in adult mice. Int J Neuropsychopharmacol 18:
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
Jørgensen, 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

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