Glycine transporter type 1 (GlyT1) inhibition improves conspecific-provoked immobility in BALB/c mice: Analysis of corticosterone response and glucocorticoid gene expression in cortex and hippocampus

Prog Neuropsychopharmacol Biol Psychiatry. 2020 Apr 20:99:109869. doi: 10.1016/j.pnpbp.2020.109869. Epub 2020 Jan 18.


Stress reactivity and glucocorticoid signaling alterations are reported in mouse models of autism spectrum disorder (ASD). BALB/c mice display decreased locomotor activity in the presence of stimulus mice and spend less time exploring enclosed stimulus mice; this mouse strain has been validated as an ASD model. VU0410120, a glycine type 1 transporter (GlyT1) inhibitor, improved sociability in BALB/c mice, consistent with data that NMDA Receptor (NMDAR) activation regulates sociability, and the endogenous tone of NMDAR-mediated neurotransmission is altered in this strain. Effects of a prosocial dose of VU0410120 on conspecific-provoked immobility, and relationships between conspecific-provoked immobility and corticosterone response were explored. VU0410120-treated BALB/c mice showed reduced immobility in the presence of conspecifics and increased the conspecific-provoked corticosterone response. However, the intensity of conspecific-provoked immobility in VU0410120-treated BALB/c mice did not differ as a function of corticosterone response. Expression profiles of 88 glucocorticoid signaling associated genes within frontal cortex and hippocampus were examined. BALB/c mice resistant to prosocial effects of VU0410120 had increased mRNA expression of Ddit4, a negative regulator of mTOR signaling. Dysregulated mTOR signaling activity is a convergent finding in several monogenic syndromic forms of ASD. Prosocial effects of VU0410120 in the BALB/c strain may be related to regulatory influences of NMDAR-activation on mTOR signaling activity. Because corticosterone response is a marker of social stress, the current data suggest that the stressfulness of a social encounter alone may not be the sole determinant of increased immobility in BALB/c mice; this strain may also display an element of social disinterest.

Keywords: Autism Spectrum disorder; BALB/c; Glucocorticoid signaling; GlyT1 inhibition; Immobility; NMDA receptor.

MeSH terms

  • Animals
  • Benzamides / pharmacology
  • Cerebral Cortex / drug effects
  • Cerebral Cortex / metabolism*
  • Corticosterone / blood*
  • Gene Expression
  • Glucocorticoids / biosynthesis*
  • Glucocorticoids / genetics
  • Glycine Plasma Membrane Transport Proteins / antagonists & inhibitors*
  • Hippocampus / drug effects
  • Hippocampus / metabolism*
  • Immobilization / physiology*
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred ICR
  • Piperidines / pharmacology
  • Receptors, N-Methyl-D-Aspartate / metabolism


  • Benzamides
  • Glucocorticoids
  • Glycine Plasma Membrane Transport Proteins
  • Piperidines
  • Receptors, N-Methyl-D-Aspartate
  • Slc6a9 protein, mouse
  • VU0410120
  • Corticosterone