BackgroundBehavioral stress is recognized as a main risk factor for neuropsychiatric diseases. Converging evidence suggested that acute stress is associated with increase of excitatory transmission in certain forebrain areas. Aim of this work was to investigate the mechanism whereby acute stress increases glutamate release, and if therapeutic drugs prevent the effect of stress on glutamate release.Methodology/FindingsRats were chronically treated with vehicle or drugs employed for therapy of mood/anxiety disorders (fluoxetine, desipramine, venlafaxine, agomelatine) and then subjected to unpredictable footshock stress. Acute stress induced marked increase in depolarization-evoked release of glutamate from synaptosomes of prefrontal/frontal cortex in superfusion, and the chronic drug treatments prevented the increase of glutamate release. Stress induced rapid increase in the circulating levels of corticosterone in all rats (both vehicle- and drug-treated), and glutamate release increase was blocked by previous administration of selective antagonist of glucocorticoid receptor (RU 486). On the molecular level, stress induced accumulation of presynaptic SNARE complexes in synaptic membranes (both in vehicle- and drug-treated rats). Patch-clamp recordings of pyramidal neurons in the prefrontal cortex revealed that stress increased glutamatergic transmission through both pre- and postsynaptic mechanisms, and that antidepressants may normalize it by reducing release probability.Conclusions/SignificanceAcute footshock stress up-regulated depolarization-evoked release of glutamate from synaptosomes of prefrontal/frontal cortex. Stress-induced increase of glutamate release was dependent on stimulation of glucocorticoid receptor by corticosterone. Because all drugs employed did not block either elevation of corticosterone or accumulation of SNARE complexes, the dampening action of the drugs on glutamate release must be downstream of these processes. This novel effect of antidepressants on the response to stress, shown here for the first time, could be related to the therapeutic action of these drugs.

Stress is a major risk factor in the onset of several neuropsychiatric disorders including anxiety and depression. Although several studies have shown that social isolation stress during postweaning period induces behavioral and brain molecular changes, the effects of social isolation on behavior during adulthood have been less characterized. Aim of this work was to investigate the relationship between the behavioral alterations and brain molecular changes induced by chronic social isolation stress in adult male mice. Plasma corticosterone levels and adrenal glands weight were also analyzed. Socially isolated (SI) mice showed higher locomotor activity, spent less time in the open field center, and displayed higher immobility time in the tail suspension test compared to group-housed (GH) mice. SI mice exhibited reduced plasma corticosterone levels and reduced difference between right and left adrenal glands. SI showed lower mRNA levels of the BDNF-7 splice variant, c-Fos, Arc, and Egr-1 in both hippocampus and prefrontal cortex compared to GH mice. Finally, SI mice exhibited selectively reduced mGluR1 and mGluR2 levels in the prefrontal cortex. Altogether, these results suggest that anxious- and depressive-like behavior induced by social isolation stress correlates with reduction of several neuroplasticity-related genes in the hippocampus and prefrontal cortex of adult male mice.

Behavioral changes in response to stressful stimuli can be controlled via adaptive epigenetic changes in neuronal gene expression. Here we indicate a role for the transcriptional corepressor Lysine-Specific Demethylase 1 (LSD1) and its dominant-negative splicing isoform neuroLSD1, in the modulation of emotional behavior. In mouse hippocampus, we show that LSD1 and neuroLSD1 can interact with transcription factor serum response factor (SRF) and set the chromatin state of SRF-targeted genes early growth response 1 (egr1) and c-fos. Deletion or reduction of neuroLSD1 in mutant mice translates into decreased levels of activating histone marks at egr1 and c-fos promoters, dampening their psychosocial stress-induced transcription and resulting in low anxiety-like behavior. Administration of suberoylanilide hydroxamine to neuroLSD1 KO mice reactivates egr1 and c-fos transcription and restores the behavioral phenotype. These findings indicate that LSD1 is a molecular transducer of stressful stimuli as well as a stress-response modifier. Indeed, LSD1 expression itself is increased acutely at both the transcriptional and splicing levels by psychosocial stress, suggesting that LSD1 is involved in the adaptive response to stress.epigenetics | stress | immediate early genes | LSD1 | SRF D ynamic changes in neuronal chromatin through histone posttranslational modifications affect complex functions such as learning, memory, and emotional behavior (1). Seminal studies have shown that mice experiencing different forms of stress, including psychosocial stress, promote stress-related plasticity through epigenetic changes at specific genes, including brain-derived neurotrophic factor (BDNF) and immediate early genes (IEGs) (2-4). These modifications induce contrasting structural and functional changes in the hippocampus and the amygdala (5), brain areas responsible for the expression of anxiety-like behavior (5-8). A decrease in neural activity in the hippocampus caused by the loss of dendritic arbors and spines is associated with posttraumatic stress disorder and recurrent depressive illness (5). Therefore, an important challenge for molecular psychiatry is a better understanding of the epigenetic regulation of plasticity gene transcription in response to stress (9).Lysine-Specific Demethylase 1 (LSD1) also known as lysine demethylase 1A (KDM1A) is an epigenetic transcriptional corepressor, tightly associated to Corepressor of REST (CoREST) and histone deacetylase 2 (HDAC2). It removes methyl groups from mono-and di-methylated lysine 4 of histone H3 (H3K4), erasing a histone mark of active transcription (10). In mammals, neurospecific splicing of microexon E8a generates the dominant-negative splicing isoform of LSD1 (neuroLSD1), which is required for the acquisition of proper neurite morphology inherent in neuronal maturation (11). Although conventional LSD1 acts as a constitutive repressor through its H3K4 demethylase activity, neuroLSD1 is unable to repress transcription (11,12). It has been shown recently that neuroLSD1 lacks d...

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New experimental evidence suggests that the mechanism of action of antidepressants includes the induction of neurotrophic factor synthesis in selected brain areas. The present study is aimed at establishing whether prolonged antidepressant treatments increase the expression of basic fibroblast growth factor (FGF2), a polypeptide growth factor that has a broad neurotrophic activity in the adult central nervous system. Rats received a single dose or long-term (3 weeks) administration of desipramine (DMI), fluoxetine (FLU), and mianserin (MIA), then were sacrificed at 5 and 24 h after the last injection. RNase protection assay and Western blot analysis revealed that all antidepressant drugs elicited an anatomically specific increase in FGF2 mRNA and protein. The increase in FGF2 mRNA after a single injection was seen only at 5 h after the injection and was restricted to the entorhinal cortex, whereas the effect of the long-term treatments lasted up to 24 h and occurred in the entire cortex and hippocampus. Immunohistochemical analysis of FGF2 immunoreactivity was carried out to investigate which cell types responded to the antidepressant treatments. DMI and MIA increased FGF2 proteins predominantly in neurons of layer V throughout the cerebral cortex and in some neurofilament-positive cells of the hippocampus. FLU increased FGF2 immunoreactivity mainly in neurofilament-positive cells of the hippocampus. These findings may explain the therapeutic efficacy of antidepressants in affective disorders.