A Functional Tph2 C1473G Polymorphism Causes an Anxiety Phenotype via Compensatory Changes in the Serotonergic System

Berger, Stefan; Weber, Tillmann; Perreau-Lenz, Stéphanie; Vogt, Miriam A.; Gartside, Sarah E.; Maser-Gluth, Christiane; Lanfumey, Laurence; Gass, Peter; Spanagel, Rainer; Bartsch, Dušan

doi:10.1038/npp.2012.46

Cited by 27 publications

(21 citation statements)

References 73 publications

(97 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Nonetheless, TPH2 expression in the dorsal raphe has repeatedly been reported to be negatively correlated with anxiety-related behavior in nulliparous female and male laboratory rodents (Gutknecht et al, 2007; Reuter et al, 2007; Beaulieu et al, 2008; Berger et al, 2012). We did not find that this relationship extended to postpartum female rats.…”

Section: Discussionmentioning

confidence: 99%

Differential postpartum sensitivity to the anxiety-modulating effects of offspring contact is associated with innate anxiety and brainstem levels of dopamine beta-hydroxylase in female laboratory rats

Ragan

Lonstein

2014

Neuroscience

View full text Add to dashboard Cite

In female mammals, the postpartum period involves dramatic shifts in many socioemotional behaviors. This includes a suppression of anxiety-related behaviors that requires recent physical contact with offspring. Factors contributing to differences among females in their susceptibility to the anxiety-modulating effect of offspring contact are unknown, but could include their innate anxiety and brain monoaminergic activity. Anxiety behavior was assessed in a large group of nulliparous female rats and the least-anxious and most-anxious tertiles were mated. Anxiety was assessed again postpartum after females were permitted or prevented from contacting their offspring 4 h before testing. Levels of dopamine β-hydroxylase (DBH, norepinephrine synthesizing enzyme) and tryptophan hydroxylase- 2 (TPH2, serotonin synthesizing enzyme) were measured in the brainstem and dorsal raphe, respectively. It was found that anxiety-related behavior in the two groups did not differ when dams were permitted contact with offspring before testing. Removal of the offspring before testing, however, differentially affected anxiety based on dams’ innate anxiety. Specifically, dams reverted back to their pre-mating levels of anxiety such that offspring removal slightly increased anxiety in the most-anxious females but greatly lowered anxiety in the least-anxious females. This reduction in anxiety in the least-anxious females after litter removal was associated with lower brainstem DBH. There was no relationship between females’ anxiety and dorsal raphe TPH2. Thus, a primary effect of recent contact with offspring on anxiety-related behavior in postpartum rats is to shift females away from their innate anxiety to a more moderate level of responding. This effect is particularly true for females with the lowest anxiety, may be mediated by central noradrenergic systems, and has implications for their ability to attend to their offspring.

show abstract

Section: Discussionmentioning

confidence: 99%

Differential postpartum sensitivity to the anxiety-modulating effects of offspring contact is associated with innate anxiety and brainstem levels of dopamine beta-hydroxylase in female laboratory rats

Ragan

Lonstein

2014

Neuroscience

View full text Add to dashboard Cite

show abstract

“…These strains did not differ in either brain 5HT levels or immobility time on the FST. 56 Similarly, Berger et al 57 showed that mice bearing the TPH2 C1473G polymorphism were not different from wild-type controls in brain 5HT content and they did not show a depression-like phenotype on the TST, FST, sucrose preference test or the LH paradigm. Taken together, our results agree with the majority of mouse genetic/strain studies and do not support a role for TPH2 or brain 5HT in the expression of a depression-like behavioral phenotype in mice.…”

Section: Va Author Manuscriptmentioning

confidence: 97%

Mice Genetically Depleted of Brain Serotonin Do Not Display a Depression-like Behavioral Phenotype

Angoa‐Pérez

Kane

Briggs

et al. 2014

ACS Chem. Neurosci.

View full text Add to dashboard Cite

Reductions in function within the serotonin (5HT) neuronal system have long been proposed as etiological factors in depression. Serotonin selective reuptake inhibitors (SSRIs) are the most common treatment for depression and their therapeutic effect is generally attributed to their ability to increase the synaptic levels of 5HT. Tryptophan hydroxylase 2 (TPH2) is the initial and ratelimiting enzyme in the biosynthetic pathway of 5HT in the CNS and losses in its catalytic activity lead to reductions in 5HT production and release. The time differential between the onset of 5HT reuptake inhibition by SSRIs (minutes) and onset of their anti-depressant efficacy (weeks to months), when considered with their overall poor therapeutic effectiveness, has cast some doubt on the role of 5HT in depression. Mice lacking the gene for TPH2 are genetically depleted of brain 5HT and were tested for a depression-like behavioral phenotype using a battery of valid tests for affective-like disorders in animals. The behavior of TPH2 −/− mice on the sucrose preference test, tail suspension test and forced swim test and their responses in the unpredictable chronic mild stress and learned helplessness paradigms was the same as wild-type controls. While TPH2−/− mice as a group were not responsive to SSRIs, a subset responded to treatment with SSRIs in the same manner as wild-type controls with significant reductions in immobility time on the tail suspension test, indicative of antidepressant drug effects. The behavioral phenotype of the TPH2 −/− mouse questions the role of 5HT in depression. Furthermore, the TPH2 −/− mouse may Detroit, MI 48201-1916. Phone: 313-476-4457, Fax: 313-576-1112. donald.kuhn@wayne.edu. Author Contributions MAP, MJK, DIB, NHM and CES conducted the in vivo behavioral and pharmacological experiments. DMF and MAP conducted the in vitro synaptosomal 5HT uptake experiments. MAP, MJK and DMK interpreted the data. MAP, MJK and DMK conceived of project and wrote the paper. All authors edited and approved the final version of the manuscript. NotesThe authors declare no competing financial interest. SUPPORTING INFORMATION AVAILABLEThe numbers of TPH2+/+ and TPH2−/− mice classified as responders or non-responders (specified by sex) to the SSRIs fluoxetine, citalopram and paroxetine is included in SI Table 1. The immobility time cutoff values for defining whether a subject was classified as a responder or non-responder to SSRIs is presented in SI Table 2. Information on the specific stressors used in the UCMS is included in SI Table 3. This information is available free of charge via the Internet at http://pubs.acs.org. U.S. Department of Veterans Affairs VA Author ManuscriptVA Author Manuscript VA Author Manuscriptserve as a useful model in the search for new medications that have therapeutic targets for depression that are outside of the 5HT neuronal system. Keywordsserotonin; TPH2; TPH2 knock out; depression-like behavior; SSRIs; SERT The serotonin (5HT) neuronal system innervates nearly the entire neuraxis from...

show abstract

“…Concentrations of monoamines and their metabolites as well as TPH2 and Tyrosine Hydroxylase (TH) activity were determined in Gria1 fl/fl and Gria1 5-HT À / À mice 4 weeks after tamoxifen treatment (Berger et al, 2012) (see Supplementary Methods for details). Using punching needles, brain region-specific tissue samples punches were acquired from brain slices (200 mm) cut on a cryostat (Leica).…”

Section: Neurochemistrymentioning

confidence: 99%

Adult AMPA GLUA1 Receptor Subunit Loss in 5-HT Neurons Results in a Specific Anxiety-Phenotype with Evidence for Dysregulation of 5-HT Neuronal Activity

Weber

Vogt

Gartside

et al. 2014

Neuropsychopharmacol

Self Cite

View full text Add to dashboard Cite

Both the glutamatergic and serotonergic (5-HT) systems are implicated in the modulation of mood and anxiety. Descending cortical glutamatergic neurons regulate 5-HT neuronal activity in the midbrain raphe nuclei through a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-D-aspartate (NMDA) receptors. To analyze the functional role of GLUA1-containing AMPA receptors in serotonergic neurons, we used the Cre-ERT2/loxP-system for the conditional inactivation of the GLUA1-encoding Gria1 gene selectively in 5-HT neurons of adult mice. These Gria1 5-HT À / À mice exhibited a distinct anxiety phenotype but showed no alterations in locomotion, depression-like behavior, or learning and memory. Increased anxiety-related behavior was associated with significant decreases in tryptophan hydroxylase 2 (TPH2) expression and activity, and subsequent reductions in tissue levels of 5-HT, its metabolite 5-hydroxyindoleacetic acid (5-HIAA), and norepinephrine in the raphe nuclei. However, TPH2 expression and activity as well as monoamine levels were unchanged in the projection areas of 5-HT neurons. Extracellular electrophysiological recordings of 5-HT neurons revealed that, while a1-adrenoceptor-mediated excitation was unchanged, excitatory responses to AMPA were enhanced and the 5-HT 1A autoreceptor-mediated inhibitory response to 5-HT was attenuated in Gria1 5-HT À / À mice. Our data show that a loss of GLUA1 protein in 5-HT neurons enhances AMPA receptor function and leads to multiple local molecular and neurochemical changes in the raphe nuclei that dysregulate 5-HT neuronal activity and induce anxiety-like behavior.

show abstract

A Functional Tph2 C1473G Polymorphism Causes an Anxiety Phenotype via Compensatory Changes in the Serotonergic System

Cited by 27 publications

References 73 publications

Differential postpartum sensitivity to the anxiety-modulating effects of offspring contact is associated with innate anxiety and brainstem levels of dopamine beta-hydroxylase in female laboratory rats

Differential postpartum sensitivity to the anxiety-modulating effects of offspring contact is associated with innate anxiety and brainstem levels of dopamine beta-hydroxylase in female laboratory rats

Mice Genetically Depleted of Brain Serotonin Do Not Display a Depression-like Behavioral Phenotype

Adult AMPA GLUA1 Receptor Subunit Loss in 5-HT Neurons Results in a Specific Anxiety-Phenotype with Evidence for Dysregulation of 5-HT Neuronal Activity

Contact Info

Product

Resources

About