Deficient serotonin neurotransmission and depression-like serotonin biomarker alterations in tryptophan hydroxylase 2 (Tph2) loss-of-function mice

Abstract

Probably the foremost hypothesis of depression is the 5-hydroxytryptamine (5-HT, serotonin) deficiency hypothesis. Accordingly, anomalies in putative 5-HT biomarkers have repeatedly been reported in depression patients. However, whether such anomalies in fact reflect deficient central 5-HT neurotransmission remains unresolved. We employed a naturalistic model of 5-HT deficiency, the tryptophan hydroxylase 2 (Tph2) R439H knockin mouse, to address this question. We report that Tph2 knockin mice have reduced basal and stimulated levels of extracellular 5-HT (5-HTExt). Interestingly, cerebrospinal fluid (CSF) 5-hydroxyindoleacetic acid (5-HIAA) and fenfluramine-induced plasma prolactin levels are markedly diminished in the Tph2 knockin mice. These data seemingly confirm that low CSF 5-HIAA and fenfluramine-induced plasma prolactin reflects chronic, endogenous central nervous system (CNS) 5-HT deficiency. Moreover, 5-HT1A receptor agonist-induced hypothermia is blunted and frontal cortex 5-HT2A receptors are increased in the Tph2 knockin mice. These data likewise parallel core findings in depression, but are usually attributed to anomalies in the respective receptors rather than resulting from CNS 5-HT deficiency. Further, 5-HT2A receptor function is enhanced in the Tph2 knockin mice. In contrast, 5-HT1A receptor levels and G-protein coupling is normal in Tph2 knockin mice, indicating that the blunted hypothermic response relates directly to the low 5-HTExt. Thus, we show that not only low CSF 5-HIAA and a blunted fenfluramine-induced prolactin response, but also blunted 5-HT1A agonist-induced hypothermia and increased 5-HT2A receptor levels are bona fide biomarkers of chronic, endogenous 5-HT deficiency. Potentially, some of these biomarkers could identify patients likely to have 5-HT deficiency. This could have clinical research utility or even guide pharmacotherapy.

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

“…Mice homozygous for the corresponding mouse Tph2 allele 1449A showed an 80% reduction of 5-HT synthesis and a strong decrease in total and extracellular 5-HT concentrations. In addition, frontal 5-HT 2A receptor function was upregulated and the 5-HT 1A -receptor agonist-induced hypothermia was blunted (Jacobsen et al, 2011), indicating 5-HT 1A autoreceptor desensitization or downregulation in serotonergic neurons of the raphe nuclei (Gross et al, 2002;Martin et al, 1992). Despite these findings and in contrast to our results, Jacobsen et al (2011) did not find altered 5-HT 1A G-protein coupling in the dorsal raphe.…”

“…We demonstrate that 1473G/G mice show a distinct anxiety phenotype, which could be observed in four different anxiety tests. A rare human G1463A TPH2 SNP was analyzed via a knock-in approach in transgenic mice (Beaulieu et al, 2008;Jacobsen et al, 2011). Mice homozygous for the corresponding mouse Tph2 allele 1449A showed an 80% reduction of 5-HT synthesis and a strong decrease in total and extracellular 5-HT concentrations.…”

“…A 'knock-in' approach was applied to study the consequences of the human TPH2 SNP G1463A (Beaulieu et al, 2008), which previously had been shown to be associated with unipolar depressive disorder (Zhang et al, 2005). The respective polymorphism (G1449A) in the mouse Tph2 gene reduced the enzymatic activity of TPH2 by 80% and led to a highly significant reduction of extracellular 5-HT concentration in several brain regions (Jacobsen et al, 2011). This correlated with an increase in anxiety-and depressionrelated behavior.…”

Transcriptional regulation of the 5-HT1Areceptor: implications for mental illness

“…For example, a reduction in TPH2 gene expression or activity [132], or reduced differentiation of 5-HT neurons as seen in Pet-1-deficient mice reduces 5-HT levels [74,75]. Hence, changes in 5-HT 1A autoreceptor levels may be secondary to or enhanced by alterations in 5-HT levels.…”

Targeting brain serotonin synthesis: insights into neurodevelopmental disorders with long-term outcomes related to negative emotionality, aggression and antisocial behaviour

“…Altered function of the PFC controlling other subcortical structures of the limbic system [106]-possibly as a consequence of increased activation of intercalated neurons residing at the boundary of the BLA to the central nucleus of the amygdala [107]-is likely to result in an increase in the frequency of inhibitory post-synaptic potentials in BLA output neurons. Recently, mice expressing the R439H TPH2 form were found to display increased cortical 5-HT 2A receptor expression due to diminished concentrations of 5-HT [20]. Tph2 þ/2 mice possess 20-30% reduced 5-HT concentrations in the rostral raphe but unaffected frontal cortex 5-HT concentrations.…”