Abstract
Early-life exposure to stress, by impacting on a brain still under development, is considered a critical factor for the increased vulnerability to psychiatric disorders and abuse of psychotropic substances during adulthood. As previously reported, rearing C57BL/6J weanling mice in social isolation (SI) from their peers for several weeks, a model of prolonged stress, is associated with a decreased plasma and brain levels of neuroactive steroids such as 3α,5α-THP, with a parallel up-regulation of extrasynaptic GABAA receptors (GABAAR) in dentate gyrus (DG) granule cells compared to group-housed (GH) mice. In the present study, together with the SI-induced decrease in plasma concentration of both progesterone and 3α,5α-THP, and an increase in THIP-stimulated GABAergic tonic currents, patch-clamp analysis of DG granule cells revealed a significant decrease in membrane input resistance and action potential (AP) firing rate, in SI compared to GH mice, suggesting that SI exerts an inhibitory action on neuronal excitability of these neurons. Voltage-clamp recordings of glutamatergic spontaneous excitatory postsynaptic currents (sEPSCs) revealed a SI-associated decrease in frequency as well as a shift from paired-pulse (PP) depression to PP facilitation (PPF) of evoked EPSCs, indicative of a reduced probability of glutamate release. Daily administration of progesterone during isolation reverted the changes in plasma 3α,5α-THP as well as in GABAergic tonic currents and neuronal excitability caused by SI, but it had only a limited effect on the changes in the probability of presynaptic glutamate release. Overall, the results obtained in this work, together with those previously published, indicate that exposure of mice to SI during adolescence reduces neuronal excitability of DG granule cells, an effect that may be linked to the increased GABAergic tonic currents as a consequence of the sustained decrease in plasma and hippocampal levels of neurosteroids. All these changes may be consistent with cognitive deficits observed in animals exposed to such type of prolonged stress.
Highlights
Prolonged stress induced by adverse events, including social isolation (SI), during early stages of life has been consistently associated with several deficits in the normal neurophysiological and neurodevelopmental processes in both humans and rodents (Hoffman-Plotkin and Twentyman, 1984; Feldman and WaltonAllen, 1997; Gottfried et al, 1998; McGue and Bouchard, 1998; Rutter, 1998; O’Connor et al, 2000; Kreppner et al, 2001)
Prolonged treatment with progesterone (5 mg/kg, s.c.) during the isolation exposure resulted in a marked elevation of its plasma concentration in both GH (one-way analysis of variance (ANOVA), F(2.9) = 10.14; p < 0.01) and SI (F(2,8) = 16.98; p < 0.001) animals which was not significantly altered by the co-treatment of finasteride (30 mg/kg, s.c.), an inhibitor of 5α-reductase, the enzyme involved in the conversion of progesterone in 3α,5α-THP (Russell and Wilson, 1994; Figure 1A)
The results of the present work demonstrate that post-weaning SI of C57BL/6J mice is accompanied by marked alterations in the passive membrane properties and excitability of dentate gyrus (DG) granule cells which appear related to the increased GABAergic inhibitory tonic currents
Summary
Prolonged stress induced by adverse events, including social isolation (SI), during early stages of life has been consistently associated with several deficits in the normal neurophysiological and neurodevelopmental processes in both humans and rodents (Hoffman-Plotkin and Twentyman, 1984; Feldman and WaltonAllen, 1997; Gottfried et al, 1998; McGue and Bouchard, 1998; Rutter, 1998; O’Connor et al, 2000; Kreppner et al, 2001). Exposure to stress during postnatal development may induce profound changes in the function of specific brain structures. SI in rodents promotes an array of behavioral, neuroendocrine, and neurochemical changes (Hall et al, 1998; Ferdman et al, 2007; Pietropaolo et al, 2008) including a sustained decrease in plasma and brain concentrations of GABAergic neuroactive steroids such as allopregnanolone (3α,5α-THP) and 3α,5α-THDOC as well as an increased expression and function of extrasynaptic α4/δ-containing GABAA receptors (GABAAR) in DG granule cells of both rats (Serra et al, 2000, 2005, 2006) and mice (Sanna et al, 2011). Neuroactive steroids produced by peripheral organs (Paul and Purdy, 1992), and synthesized de novo in the brain (defined as neurosteroids; Hu et al, 1987; Mathur et al, 1993) from their precursor progesterone, regulate neuronal excitability acting mainly as potent positive modulators of GABAAR, those containing the δ subunit that are located at extrasynaptic sites and are responsible for generating tonic inhibitory currents (Nusser et al, 1995; Glykys and Mody, 2007; Glykys et al, 2008)
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