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The repeated maternal separation (RMS) is a useful experimental model useful in rodents to study the long-term influence of early-life stress on brain neurophysiology. We here investigated the influence of RMS exposure on hippocampal inhibitory and excitatory synaptic transmission, long-term synaptic plasticity and the related potential alterations in learning and memory performance in adult male and female C57Bl/6J mice. Mice were separated daily from their dam for 360 min, from postnatal day 2 (PND2) to PND17, and experiments were performed at PND 60. Patch-clamp recordings in hippocampal CA1 pyramidal neurons revealed a significant enhancement of GABAergic miniature IPSC (mIPSC) frequency, and a decrease in the amplitude of glutamatergic mEPSCs in male mice exposed to RMS. Only a slight but significant reduction in the amplitude of GABAergic mIPSCs was observed in females exposed to RMS compared to the relative controls. A marked increase in long-term depression (LTD) at CA3-CA1 glutamatergic synapses and in the response to the CB1r agonist win55,212 were detected in RMS male, but not female mice. An impaired spatial memory and a reduced preference for novelty was observed in males exposed to RMS but not in females. A single injection of β-ethynyl estradiol at PND2, prevented the changes observed in RMS male mice, suggesting that estrogens may play a protective role early in life against the exposure to stressful conditions. Our findings strengthen the idea of a sex-dependent influence of RMS on long-lasting modifications in synaptic transmission, effects that may be relevant for cognitive performance.

Environmental enrichment is known to improve brain plasticity and protect synaptic function from negative insults. In the present study we used the exposure to social enrichment to ameliorate the negative effect observed in post weaning isolated male rats in which neurotrophic factors, neurogenesis, neuronal dendritic trees and spines were altered markedly in the hippocampus. After the 4 weeks of post-weaning social isolation followed by 4 weeks of reunion, different neuronal growth markers as well as neuronal morphology were evaluated using different experimental approaches. Social enrichment restored the reduction of BDNF, NGF and Arc gene expression in the whole hippocampus of social isolated rats. This effect was paralleled by an increase in density and morphology of dendritic spines, as well as in neuronal tree arborisation in granule cells of the dentate gyrus. These changes were associated with a marked increase in neuronal proliferation and neurogenesis in the same hippocampal subregion that were reduced by social isolation stress. These results further suggest that the exposure to social enrichment, by abolishing the negative effect of social isolation stress on hippocampal plasticity, may improve neuronal resilience with a beneficial effect on cognitive function.

Thiocolchicoside (TCC) is used clinically for its muscle relaxant, anti-inflammatory, and analgesic properties, and it has been shown to interact with gamma-aminobutyric acid (GABA) type A receptors (GABAARs) and strychnine-sensitive glycine receptors in the rat central nervous system. In contrast to a proposed agonistic action at these two types of inhibitory receptors, pharmacological evidence has shown that, under certain conditions, TCC manifests convulsant activity in animals and humans. We now show that the phasic and tonic GABAAR-mediated currents recorded from Purkinje cells and granule neurons, respectively, in parasagittal cerebellar slices from adult male rats were inhibited by TCC in a concentration-dependent manner. The median inhibitory concentrations of TCC for these effects were approximately 0.15 and approximately 0.9 microM, respectively. TCC did not potentiate GABABR-mediated currents in hippocampal slices, suggesting that its muscle relaxant action is not mediated by GABABRs. Intraperitoneal injection of TCC in rats either alone or in combination with negative modulators of GABAergic transmission revealed convulsant and proconvulsant actions of this drug. Our data, consistent with clinical observations of the epileptogenic effect of this compound, suggest that TCC is a potent competitive antagonist of GABAAR function.