Epigenetic mechanisms are involved in the pathophysiology of depressive disorders and are unique potential targets for therapeutic intervention. The acetylating agent L-acetylcarnitine (LAC), a welltolerated drug, behaves as an antidepressant by the epigenetic regulation of type 2 metabotropic glutamate (mGlu2) receptors. It caused a rapid and long-lasting antidepressant effect in Flinders Sensitive Line rats and in mice exposed to chronic unpredictable stress, which, respectively, model genetic and environmentally induced depression. In both models, LAC increased levels of acetylated H3K27 bound to the Grm2 promoter and also increased acetylation of NF-ĸB-p65 subunit, thereby enhancing the transcription of Grm2 gene encoding for the mGlu2 receptor in hippocampus and prefrontal cortex. Importantly, LAC reduced the immobility time in the forced swim test and increased sucrose preference as early as 3 d of treatment, whereas 14 d of treatment were needed for the antidepressant effect of chlorimipramine. Moreover, there was no tolerance to the action of LAC, and the antidepressant effect was still seen 2 wk after drug withdrawal. Conversely, NF-ĸB inhibition prevented the increase in mGlu2 expression induced by LAC, whereas the use of a histone deacetylase inhibitor supported the epigenetic control of mGlu2 expression. Finally, LAC had no effect on mGlu2 knockout mice exposed to chronic unpredictable stress, and a single injection of the mGlu2/3 receptor antagonist LY341495 partially blocked LAC action. The rapid and long-lasting antidepressant action of LAC strongly suggests a unique approach to examine the epigenetic hypothesis of depressive disorders in humans, paving the way for more efficient antidepressants with faster onset of action.BDNF | histone acetylation | MDD | glutamatergic neurotransmission | chromatin

Recent studies have implicated brain-derived neurotrophic factor (BDNF) in the pathophysiology of depression and the activity of antidepressant drugs. Serum BDNF levels are lower in depressed patients, and increase in response to antidepressant medication. However, how BDNF responds to different classes of antidepressant drugs is unknown. We assessed serum BDNF levels in 21 patients with major depressive episode treated with sertraline, escitalopram, or venlafaxine and 20 healthy controls. Serum samples were collected between 10 a.m. and 12 p.m. at baseline, 5 weeks, and 6 months of treatment. BDNF levels were measured via immunoassay. The severity of symptoms and response to treatment were assessed by the Hamilton rating scales for depression (HRSD). Baseline serum BDNF levels were significantly lower in depressed patients compared to controls. Sertraline increased BDNF levels after 5 weeks and 6 months of treatment. Venlafaxine increased BDNF levels only after 6 months. Escitalopram did not affect BDNF levels at either time point. A significant negative association was found between percentage increase in BDNF levels and percentage decreased in HRSD scores after 6 months of treatment. In conclusion, these results suggest that different antidepressant drugs have variable effects on serum BDNF levels. This is true even though the three different drugs were equally effective in relieving symptoms of depression and anxiety.

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Excitatory amino acids play a key role in both adaptive and deleterious effects of stressors on the brain, and dysregulated glutamate homeostasis has been associated with psychiatric and neurological disorders. Here, we elucidate mechanisms of epigenetic plasticity in the hippocampus in the interactions between a history of chronic stress and familiar and novel acute stressors that alter expression of anxiety-and depressive-like behaviors. We demonstrate that acute restraint and acute forced swim stressors induce differential effects on these behaviors in naive mice and in mice with a history of chronic-restraint stress (CRS). They reveal a key role for epigenetic up-and down-regulation of the putative presynaptic type 2 metabotropic glutamate (mGlu2) receptors and the postsynaptic NR1/NMDA receptors in the hippocampus and particularly in the dentate gyrus (DG), a region of active neurogenesis and a target of antidepressant treatment. We show changes in DG long-term potentiation (LTP) that parallel behavioral responses, with habituation to the same acute restraint stressor and sensitization to a novel forced-swim stressor. In WT mice after CRS and in unstressed mice with a BDNF loss-of-function allele (BDNF Val66Met), we show that the epigenetic activator of histone acetylation, P300, plays a pivotal role in the dynamic up-and down-regulation of mGlu2 in hippocampus via histone-3-lysine-27-acetylation (H3K27Ac) when acute stressors are applied. These hippocampal responses reveal a window of epigenetic plasticity that may be useful for treatment of disorders in which glutamatergic transmission is dysregulated.S tress effects on higher brain regions, such as hippocampus, are known to involve actions of excitatory amino acids to induce structural and functional changes depending upon the type, intensity, and duration of the stressor (1). These differential responses, including determining susceptibility versus resilience to stress, contribute to the pathophysiology of debilitating stress-related disorders (2-5). The hippocampus is a brain region noted for its plasticity in response to stress and sensitivity to adrenal steroid hormones (6). Acute stress enhances synaptic plasticity that is associated with improved cognition and other adaptive functions whereas chronic stress produces opposite effects mediating, in the hippocampus, spine synapse turnover, dendritic shrinkage, impaired long-term potentiation (LTP), and suppression of adult neurogenesis in the dentate gyrus (DG) (1, 7). Importantly, neuroanatomical changes in response to repeated stress recover in young adult animals, based upon the restoration of dendritic length and branching and spine density (8). However, there are underlying changes that can be seen at the level of gene expression and epigenetic regulation that indicate that the brain is continually changing (9, 10). Epigenetic modifications, such as acetylation of histones, have also been involved in the consolidation of contextual memories that allow the brain to respond and adapt to changes in ...

The kynurenine pathway of tryptophan metabolism has been implicated in the pathophysiology of psychiatric disorders, including schizophrenia. We report here that the kynurenine metabolite, xanturenic acid (XA), interacts with, and activates mGlu2 and mGlu3 metabotropic glutamate receptors in heterologous expression systems. However, the molecular nature of this interaction is unknown, and our data cannot exclude that XA acts primarily on other targets, such as the vesicular glutamate transporter, in the CNS. Systemic administration of XA in mice produced antipsychotic-like effects in the MK-801-induced model of hyperactivity. This effect required the presence of mGlu2 receptors and was abrogated by the preferential mGlu2/3 receptor antagonist, LY341495. Because the mGlu2 receptor is a potential drug target in the treatment of schizophrenia, we decided to measure serum levels of XA and other kynurenine metabolites in patients affected by schizophrenia. Serum XA levels were largely reduced in a large cohort of patients affected by schizophrenia, and, in patients with first-episode schizophrenia, levels remained low after 12 months of antipsychotic medication. As opposed to other kynurenine metabolites, XA levels were also significantly reduced in first-degree relatives of patients affected by schizophrenia. We suggest that lowered serum XA levels might represent a novel trait marker for schizophrenia.

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