Long lasting effects of early-life stress on glutamatergic/GABAergic circuitry in the rat hippocampus

Neuropharmacology. 2012 Apr;62(5-6):1944-53. doi: 10.1016/j.neuropharm.2011.12.019. Epub 2012 Jan 4.


The objective of the present work was to study the effects of an early-life stress (maternal separation, MS) in the excitatory/inhibitory ratio as a potential factor contributing to the ageing process, and the purported normalizing effects of chronic treatment with the antidepressant venlafaxine. MS induced depressive-like behaviour in the Porsolt forced swimming test that was reversed by venlafaxine, and that persisted until senescence. Aged MS rats showed a downregulation of vesicular glutamate transporter 1 and 2 (VGlut1 and VGlut2) and GABA transporter (VGAT) and increased expression of excitatory amino acid transporter 2 (EAAT2) in the hippocampus. Aged rats showed decreased expression of glutamic acid decarboxylase 65 (GAD65), while the excitatory amino acid transporter 1 (EAAT1) was affected only by stress. Glutamate receptor subunits NR1 and NR2A and GluR4 were upregulated in stressed rats, and this effect was reversed by venlafaxine. NR2B, GluR1 and GluR2/3 were not affected by either stress or age. MS, both in young and aged rats, induced an increase in the circulating levels of corticosterone. Corticosterone induced an increase glutamate and a decrease in GABA release in hippocampal slices, which was reversed by venlafaxine. Chronic treatment with corticosterone recapitulated the main biochemical findings observed in MS. The different effects that chronic stress exerts in young and adult animals on expression of proteins responsible for glutamate/GABA cycling may explain the involvement of glucocorticoids in ageing-related diseases. Modulation of glutamate/GABA release may be a relevant component of the therapeutic action of antidepressants, such as venlafaxine.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Age Factors
  • Animals
  • Antidepressive Agents, Second-Generation / pharmacology
  • Antidepressive Agents, Second-Generation / therapeutic use
  • Corticosterone / blood
  • Cyclohexanols / pharmacology
  • Cyclohexanols / therapeutic use
  • Depression / drug therapy
  • Depression / metabolism*
  • Depression / physiopathology
  • Excitatory Amino Acid Transporter 1 / metabolism
  • Female
  • GABA Plasma Membrane Transport Proteins / metabolism
  • Glutamate Decarboxylase / metabolism
  • Glutamic Acid / metabolism*
  • Hippocampus / metabolism*
  • Hippocampus / physiopathology
  • Male
  • Maternal Deprivation*
  • Nerve Net / metabolism*
  • Nerve Net / physiopathology
  • Neurons / metabolism*
  • Rats
  • Venlafaxine Hydrochloride
  • gamma-Aminobutyric Acid / metabolism*


  • Antidepressive Agents, Second-Generation
  • Cyclohexanols
  • Excitatory Amino Acid Transporter 1
  • GABA Plasma Membrane Transport Proteins
  • Slc1a3 protein, rat
  • Glutamic Acid
  • gamma-Aminobutyric Acid
  • Venlafaxine Hydrochloride
  • Glutamate Decarboxylase
  • Corticosterone