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

Mol Psychiatry. 2012 Jul;17(7):694-704. doi: 10.1038/mp.2011.50. Epub 2011 May 3.


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-HT(Ext)). 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-HT(1A) receptor agonist-induced hypothermia is blunted and frontal cortex 5-HT(2A) 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-HT(2A) receptor function is enhanced in the Tph2 knockin mice. In contrast, 5-HT(1A) receptor levels and G-protein coupling is normal in Tph2 knockin mice, indicating that the blunted hypothermic response relates directly to the low 5-HT(Ext). Thus, we show that not only low CSF 5-HIAA and a blunted fenfluramine-induced prolactin response, but also blunted 5-HT(1A) agonist-induced hypothermia and increased 5-HT(2A) 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Behavior, Animal / drug effects
  • Behavior, Animal / physiology
  • Biomarkers / blood
  • Biomarkers / cerebrospinal fluid
  • Biomarkers / metabolism
  • Corticosterone / blood
  • Depression / blood*
  • Depression / cerebrospinal fluid
  • Depression / genetics
  • Disease Models, Animal
  • Extracellular Fluid / metabolism
  • Female
  • Fenfluramine / pharmacology
  • Frontal Lobe / metabolism
  • Gene Knock-In Techniques / methods
  • Gene Knock-In Techniques / psychology
  • Hippocampus / metabolism
  • Hydroxyindoleacetic Acid / cerebrospinal fluid*
  • Hypothermia / chemically induced
  • Hypothermia / physiopathology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Prolactin / blood
  • Receptor, Serotonin, 5-HT1A / genetics
  • Receptor, Serotonin, 5-HT1A / metabolism
  • Receptor, Serotonin, 5-HT2A / genetics
  • Receptor, Serotonin, 5-HT2A / metabolism*
  • Serotonergic Neurons / drug effects
  • Serotonergic Neurons / enzymology
  • Serotonergic Neurons / physiology*
  • Serotonin / deficiency*
  • Serotonin / metabolism
  • Serotonin 5-HT1 Receptor Agonists / pharmacology
  • Synaptic Transmission / drug effects
  • Synaptic Transmission / genetics
  • Synaptic Transmission / physiology*
  • Tryptophan Hydroxylase / genetics
  • Tryptophan Hydroxylase / physiology*


  • Biomarkers
  • Receptor, Serotonin, 5-HT2A
  • Serotonin 5-HT1 Receptor Agonists
  • Receptor, Serotonin, 5-HT1A
  • Fenfluramine
  • Serotonin
  • Hydroxyindoleacetic Acid
  • Prolactin
  • Tph2 protein, mouse
  • Tryptophan Hydroxylase
  • Corticosterone