Elsevier

Neuropharmacology

Volume 62, Issues 5–6, April 2012, Pages 1944-1953
Neuropharmacology

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

https://doi.org/10.1016/j.neuropharm.2011.12.019Get rights and content

Abstract

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.

Highlights

► Aged stressed rats showed an altered expression of VGlut1, VGlut2, VGAT and EAAT2. ► GAD65 expression was increased in aged rats, and EAAT1 was affected only by stress. ► Upregulation of NR1, NR2A and GluR4 induced by stress was reversed by venlafaxine. ► Both young and aged MS exhibited an increase in the circulating corticosterone. ► Altered glutamate/GABA release after corticosterone was reversed by venlafaxine.

Introduction

Stress is believed to contribute to the variability of the ageing process and to the development of age-related neuro- and psychopathologies (Heim and Nemeroff, 1999; McEwen, 2002; Miller and O'Callaghan, 2005). In fact, the experience of stress or traumatic experience early in life is thought to make an individual more vulnerable for psychiatric problems, such as depression or anxiety, later in life (Gilmer and McKinney, 2003; Heim and Nemeroff, 2001).

Abnormalities in glutamate and gamma-aminobutyric acid (GABA) signal transmission have been postulated to play a role in depression (Krystal et al., 2002). Increased glutamate and reduced GABA levels have been observed in the cortex of depressed patients, leading to an enhanced excitatory–inhibitory ratio (Bhagwagar et al., 2007; Sanacora et al., 1999). Interestingly, this imbalance is inhibited by chronic treatment with antidepressants (Sanacora et al., 2002). Because the presynaptic pathways regulating the synthesis and cycling of glutamate and GABA are tightly coupled, it has been suggested that alterations in a shared pathway may account for the observed amino acid abnormalities. For instance, post-mortem studies have shown decreased expression of glutamic acid decarboxylase 65 (GAD65), the enzyme that convert glutamate to GABA, in mood disorders (Fatemi et al., 2005). Microarray analysis of cerebral cortex from individuals who had suffered from major depression disorder have demonstrated significant downregulation of the glial excitatory amino acid transporter 1 and 2 (EAAT1 and EAAT2), key members of the glutamate/neutral amino acid transporter protein family (Choudary et al., 2005). At the experimental level, decrease of the vesicular GABA transporter (VGAT), and GAD65 and an upregulation of EAAT1 has been shown in the hippocampus of animals subjected to chronic stress when adults (chronic mild stress, CMS, Garcia-Garcia et al., 2009). Mice heterozygous for the vesicular glutamate transporter 1 (VGLUT1 +/−) showed increased depressive-like behavioural symptoms as well as increased neuronal synthesis of glutamate and decreased hippocampal GABA, VGLUT1, and EAAT1 levels (Garcia-Garcia et al., 2009).

Emotional experience during early life has been shown to interfere with the development of excitatory synaptic networks in hippocampus of rodents. Maternal separation (MS) is an animal paradigm designed to mimic repeated exposure to stress during early life, resulting in animals with behavioural and neuroendocrine signs of elevated stress reactivity as adults (Aisa et al., 2007; Heim and Nemeroff, 2001; Lehmann and Feldon, 2000) or senescent (Solas et al., 2010). The peak period of neurogenesis overlaps the stress hyporesponsive period (postnatal days 4–14) in neonatal rats (Sapolsky and Meaney, 1986). Therefore, early stress, such as MS, could be interfering with the normal maturation of excitatory/inhibitory synapses in the hippocampus, which might ultimately lead to an increased vulnerability for psychiatric diseases. To test this hypothesis, we have studied the lasting consequences of early-life stress exposure on the expression of presynaptic proteins involved in the glutamate/GABA cycle and on the expression of different glutamate receptor subunits in the hippocampus of young and aged rats. In addition, we have checked if the treatment with the antidepressant venlafaxine in adulthood could be effective in preventing the purported interaction between ageing and stress. Finally, as acute stress is known to increase glutamate release (Gould et al., 2000; Lowy et al., 1993; Musazzi et al., 2010), the effects of the stress hormone corticosterone on glutamate/GABA release “in vitro” have been checked.

Section snippets

Animals

All the experiments were carried out in strict compliance with the recommendations of the EU (86/609/EEC) for the care and use of laboratory animals. All efforts were made to minimise animal suffering, to reduce the number of animals, and alternative to in vivo techniques (in vitro release experiments) have been used. Timed-pregnant Wistar rats were provided on gestation day 16 from Charles River Laboratories (Portage, MI, USA), individually housed in a temperature (21 ± 1 °C) and humidity

Depressive-like behaviour

In the forced swimming test (Fig. 1A), two-way ANOVA indicated a significant main effect of stress [F1,82 = 17.217, p < 0.001; n = 10 per group]. Venlafaxine treatment (Fig. 1B) reversed the depressive phenotype associated to MS in young rats [significant interaction stress × treatment, F1,59 = 3.386, p < 0.05; n = 10 per group].

Regulation of presynaptic proteins

As shown in Fig. 2, aged MS rats showed decreased expression of VGlut1 [significant interaction stress × age, F1,35 = 11.239, p < 0.05; n = 9 per group]. A specific

Discussion

Stressful life events are known to precipitate mood/anxiety disorders. In fact, experimental models of chronic stress are considerer nowadays as useful models to study depression. The effects of early-life stress endure and worsen during ageing (Solas et al., 2010), yet the mechanisms for these purportedly clinically important sequelae are poorly understood. It has been suggested that maladaptive changes in excitatory/inhibitory circuitry have a primary role in the pathophysiology of mood

Acknowledgements

Authors thank Ms. M. Luz Muro for her excellent technical assistance. This work has been supported by the Newmood integrated project (EC, LSHM-CT-2004-503474) and “Tu eliges, Tu decides” projects of CAN.

All authors disclose any actual or potential conflict of interest including any financial, personal or other relationships with both organizations that sponsored the research.

References (48)

  • C.O. Ladd et al.

    Long-term behavioral and neuroendocrine adaptations to adverse early experience

    Prog. Brain Res.

    (2000)
  • J. Liang et al.

    Excitatory amino acid transporter expression by astrocytes is neuroprotective against microglial excitotoxicity

    Brain Res.

    (2008)
  • B.S. McEwen

    Sex, stress and the hippocampus: allostasis, allostatic load and the aging process

    Neurobiol. Aging

    (2002)
  • D.B. Miller et al.

    Aging, stress and the hippocampus

    Ageing Res. Rev.

    (2005)
  • L. Musazzi et al.

    Stress, glucocorticoids and glutamate release: effects of antidepressant drugs

    Neurochem. Int.

    (2011)
  • C.M. Pariante et al.

    The HPA axis in major depression: classical theories and new developments

    Trends Neurosci.

    (2008)
  • C. Pickering et al.

    Repeated maternal separation of male Wistar rats alters glutamate receptor expression in the hippocampus but not the prefrontal cortex

    Brain Res.

    (2006)
  • C.R. Pryce et al.

    Long-term effects of early-life environmental manipulations in rodents and primates: potential animal models in depression research

    Neurosci. Biobehav. Rev.

    (2005)
  • T. Rauen et al.

    Fine tuning of glutamate uptake and degradation in glial cells: common transcriptional regulation of GLAST1 and GS

    Neurochem. Int.

    (2000)
  • R.M. Sapolsky et al.

    Maturation of the adreno-cortical stress response: neuroendocrine control mechanisms and the stress hyporesponsive period

    Brain Res. Rev.

    (1986)
  • R.M. Sapolsky et al.

    The adrenocortical stress-response in the aged male rat: impairment of recovery from stress

    Exp. Gerontol.

    (1983)
  • R.M. Sapolsky et al.

    The adrenocortical axis in the aged rat: impaired sensitivity to both fast and delayed feedback inhibition

    Neurobiol. Aging

    (1986)
  • J. Born et al.

    Effects of age and gender on pituitary–adrenocortical responsiveness in humans

    Eur. J. Endocrinol.

    (1995)
  • P.V. Choudary et al.

    Altered cortical glutamatergic and GABAergic signal transmission with glial involvement in depression

    Proc. Natl. Acad. Sci. U S A

    (2005)
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