Social approach, anxiety, and altered tryptophan hydroxylase 2 activity in juvenile BALB/c and C57BL/6J mice

Behav Brain Res. 2019 Feb 1:359:918-926. doi: 10.1016/j.bbr.2018.06.019. Epub 2018 Jun 20.


Autism spectrum disorder (ASD) is a heterogeneous and highly heritable condition with multiple aetiologies. Although the biological mechanisms underlying ASD are not fully understood, evidence suggests that dysregulation of serotonergic systems play an important role in ASD psychopathology. Preclinical models using mice with altered serotonergic neurotransmission may provide insight into the role of serotonin in behaviours relevant to clinical features of ASD. For example, BALB/c mice carry a loss-of-function single nucleotide polymorphism (SNP; C1473 G) in tryptophan hydroxylase 2 (Tph2), which encodes the brain-specific isoform of the rate-limiting enzyme for serotonin synthesis, and these mice frequently have been used to model symptoms of ASD. In this study, juvenile male BALB/c (G/G; loss-of-function variant) and C57BL/6 J (C/C; wild type variant) mice, were exposed to the three-chamber sociability test, and one week later to the elevated plus-maze (EPM). Tryptophan hydroxylase 2 (TPH2) activity was measured following injection of the aromatic amino acid decarboxylase (AADC)-inhibitor, NSD-1015, and subsequent HPLC detection of 5-hydroxytryptophan (5-HTP) within subregions of the dorsal raphe nucleus (DR) and median raphe nucleus (MnR). The BALB/c mice showed reduced social behaviour and increased anxious behaviour, as well as decreased 5-HTP accumulation in the rostral and mid-rostrocaudal DR. In the full cohort of mice, TPH2 activity in the mid-rostrocaudal DR was correlated with anxious behaviour in the EPM, however these correlations were not statistically significant within each strain, suggesting that TPH2 activity was not directly associated with either anxiety or sociability. Further research is therefore required to more fully understand how serotonergic systems are involved in mouse behaviours that resemble some of the clinical features of ASD.

Keywords: Autism; Dorsal raphe nucleus; Serotonin; Tryptophan hydroxylase 2.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Age Factors
  • Analysis of Variance
  • Animals
  • Animals, Newborn
  • Anxiety / drug therapy
  • Anxiety / metabolism*
  • Enzyme Inhibitors / pharmacology
  • Gene Expression Regulation / drug effects
  • Genotype
  • Humans
  • Hydrazines / therapeutic use
  • Male
  • Maze Learning / drug effects
  • Maze Learning / physiology
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Raphe Nuclei / metabolism*
  • Social Behavior*
  • Species Specificity
  • Tryptophan Hydroxylase / genetics
  • Tryptophan Hydroxylase / metabolism*


  • Enzyme Inhibitors
  • Hydrazines
  • 3-hydroxybenzylhydrazine
  • Tph2 protein, mouse
  • Tryptophan Hydroxylase