Epigenetic regulation of metabotropic glutamate 2/3 receptors: Potential role for ultra-resistant schizophrenia?

Schizophrenia is a severe and debilitating psychiatric disorder characterized by early cognitive deficits, emotional and behavioral abnormalities resulted by a dysfunctional gene x environment interaction. Genetic and epigenetic abnormalities in cortical parvalbumin-positive GABAergic interneurons lead to alterations in glutamate-mediated excitatory neurotransmission, synaptic plasticity, and neuronal development. Epigenetic alterations during pregnancy or early phases of postnatal life are associated with schizophrenia vulnerability as well as inflammatory processes which are at the basis of brain pathology.

The Strategy of Targeting Peroxisome Proliferator-Activated Receptor (PPAR) in the Treatment of Neuropsychiatric Disorders.

Peroxisome proliferator-activated receptors (PPARs) are nonsteroid nuclear receptors and transcription factors that regulate several neuroinflammatory and metabolic processes, recently involved in several neuropsychiatric conditions, including Alzheimer's disease, Parkinson's disease, major depressive disorder, post-traumatic stress disorder (PTSD), schizophrenia spectrum disorders, and autism spectrum disorders. PPARs are ligand-activated receptors that, following stimulation, induce neuroprotective effects by decreasing neuroinflammatory processes through inhibition of the nuclear factor kappa-light-chain-enhancer of activated B cell (NF-κB) expression and consequent suppression of pro-inflammatory cytokine production. PPARs heterodimerize with the retinoid X-receptor (RXR) and bind to PPAR-responsive regulatory elements (PPRE) in the promoter region of target genes involved in lipid metabolism, synthesis of cholesterol, catabolism of amino acids, and inflammation.

Functional Nutrition as Integrated Intervention for In- and Outpatient with Schizophrenia.

Schizophrenia is a chronic and progressive disorder characterized by cognitive, emotional, and behavioral abnormalities associated with neuronal development and synaptic plasticity alterations. Genetic and epigenetic abnormalities in cortical parvalbumin-positive GABAergic interneurons and consequent alterations in glutamate-mediated excitatory neurotransmission during early neurodevelopment underlie schizophrenia manifestation and progression. Also, epigenetic alterations during pregnancy or early phases of postnatal life are associated with schizophrenia vulnerability and inflammatory processes, which are at the basis of brain pathology and a higher risk of comorbidities, including cardiovascular diseases and metabolic syndrome.

Altered Expression and Activity of mGlu5 Variant a Receptors in the Striatum of BTBR Mice: Novel Insights Into the Pathophysiology of Adult Idiopathic Forms of Autism Spectrum Disorders.

Background: mGlu5 metabotropic glutamate receptors are considered as candidate drug targets in the treatment of "monogenic" forms of autism spectrum disorders (ASD), such as Fragile- X syndrome (FXS). However, despite promising preclinical data, clinical trials using mGlu5 receptor antagonists to treat FXS showed no beneficial effects.

Objective: Here, we studied the expression and function of mGlu5 receptors in the striatum of adult BTBR mice, which model idiopathic forms of ASD, and behavioral phenotype.

PPAR and functional foods: Rationale for natural neurosteroid-based interventions for postpartum depression.

Allopregnanolone, a GABAergic neurosteroid and progesterone derivative, was recently approved by the Food and Drug Administration for the treatment of postpartum depression (PPD). Several mechanisms appear to be involved in the pathogenesis of PPD, including neuroendocrine dysfunction, neuroinflammation, neurotransmitter alterations, genetic and epigenetic modifications. Recent evidence highlights the higher risk for incidence of PPD in mothers exposed to unhealthy diets that negatively impact the microbiome composition and increase inflammation, all effects that are strongly correlated with mood disorders.

Targeting mGlu Receptors for Optimization of Antipsychotic Activity and Disease-Modifying Effect in Schizophrenia.

Metabotropic glutamate (mGlu) receptors are considered as candidate drug targets for the treatment of schizophrenia. These receptors form a family of eight subtypes (mGlu1 to -8), of which mGlu1 and -5 are coupled to G, and all other subtypes are coupled to G. Here, we discuss the possibility that selective ligands of individual mGlu receptor subtypes may be effective in controlling the core symptoms of schizophrenia, and, in some cases, may impact mechanisms underlying the progression of the disorder.

Epigenetic Alterations in Prenatal Stress Mice as an Endophenotype Model for Schizophrenia: Role of Metabotropic Glutamate 2/3 Receptors.

Mice subjected to prenatal restraint stress ( mice) showed biochemical and behavioral abnormalities consistent with a schizophrenia-like phenotype (Matrisciano et al., 2016). PRS mice are characterized by increased DNA-methyltransferase 1 (DNMT1) and ten-eleven methylcytosine dioxygenase 1 (TET1) expression levels and exhibit an enrichment of 5-methylcytosine (5MC) and 5-hydroxymethylcytosine (5HMC) at neocortical GABAergic and glutamatergic gene promoters.

The allosteric dopamine D1 receptor potentiator, DETQ, ameliorates subchronic phencyclidine-induced object recognition memory deficits and enhances cortical acetylcholine efflux in male humanized D1 receptor knock-in mice.

Diminished dopamine D1 stimulation may contribute to cognitive impairment in Alzheimer's and Parkinson's diseases, schizophrenia, and other neuropsychiatric disorders. However, orthosteric D1 receptor (D1R) agonists produce receptor desensitization and an inverted U-shaped dose-response curve, but positive allosteric modulators (PAMs) do not. We examined the cognitive effects of DETQ, a D1R PAM, in mice genetically modified to express the human D1 receptor ("hD1 mice").

The impact of metabotropic glutamate receptors into active neurodegenerative processes: A "dark side" in the development of new symptomatic treatments for neurologic and psychiatric disorders.

Metabotropic glutamate (mGlu) receptor ligands are under clinical development for the treatment of CNS disorders with high social and economic burden, such as schizophrenia, major depressive disorder (MDD), and Parkinson's disease (PD), and are promising drug candidates for the treatment of Alzheimer's disease (AD). So far, clinical studies have shown symptomatic effects of mGlu receptor ligands, but it is unknown whether these drugs act as disease modifiers or, at the opposite end, they accelerate disease progression by enhancing neurodegeneration. This is a fundamental issue in the treatment of PD and AD, and is also an emerging theme in the treatment of schizophrenia and MDD, in which neurodegeneration is also present and contribute to disease progression.

Metabotropic Glutamate 2/3 Receptors and Epigenetic Modifications in Psychotic Disorders: A Review.

Schizophrenia and Bipolar Disorder are chronic psychiatric disorders, both considered as "major psychosis"; they are thought to share some pathogenetic factors involving a dysfunctional gene x environment interaction. Alterations in the glutamatergic transmission have been suggested to be involved in the pathogenesis of psychosis. Our group developed an epigenetic model of schizophrenia originated by Prenatal Restraint Stress (PRS) paradigm in mice.

Brain-derived neurotrophic factor epigenetic modifications associated with schizophrenia-like phenotype induced by prenatal stress in mice.

Background: Prenatal stress (PRS) is considered a risk factor for several neurodevelopmental disorders including schizophrenia (SZ). An animal model involving restraint stress of pregnant mice suggests that PRS induces epigenetic changes in specific GABAergic and glutamatergic genes likely to be implicated in SZ, including the gene for brain-derived neurotrophic factor (BDNF).

Methods: Studying adult offspring of pregnant mice subjected to PRS, we explored the long-term effects of PRS on behavior and on the expression of key chromatin remodeling factors including DNA methyltransferase 1, ten-eleven-translocation hydroxylases, methyl CpG binding protein 2, histone deacetylases, and histone methyltransferases and demethylase in the frontal cortex and hippocampus.

Levels of the Rab GDP dissociation inhibitor (GDI) are altered in the prenatal restrain stress mouse model of schizophrenia and are differentially regulated by the mGlu2/3 receptor agonists, LY379268 and LY354740.

LY379268 and LY354740, two agonists of mGlu2/3 metabotropic glutamate receptors, display different potencies in mouse models of schizophrenia. This differential effect of the two drugs remains unexplained. We performed a proteomic analysis in cultured cortical neurons challenged with either LY379268 or LY354740.

L-acetylcarnitine causes rapid antidepressant effects through the epigenetic induction of mGlu2 receptors.

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 well-tolerated 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.

Exposure to predator odor and resulting anxiety enhances the expression of the α2 δ subunit of voltage-sensitive calcium channels in the amygdala.

The α2 δ subunit of voltage-sensitive calcium channels (VSCCs) is the molecular target of pregabalin and gabapentin, two drugs marked for the treatment of focal epilepsy, neuropathic pain, and anxiety disorders. Expression of the α2 δ subunit is up-regulated in the dorsal horns of the spinal cord in models of neuropathic pain, suggesting that plastic changes in the α2 δ subunit are associated with pathological states. Here, we examined the expression of the α2 δ-1 subunit in the amygdala, hippocampus, and frontal cortex in the trimethyltiazoline (TMT) mouse model of innate anxiety.

Enhanced mGlu5-receptor dependent long-term depression at the Schaffer collateral-CA1 synapse of congenitally learned helpless rats.

Alterations of the glutamatergic system have been implicated in the pathophysiology and treatment of major depression. In order to investigate the expression and function of mGlu5 receptors in an animal model for treatment-resistant depression we used rats bred for congenital learned helplessness (cLH) and the control strain, bred for resistance against inescapable stress, congenitally. not learned helpless rats (cNLH).

mGlu2/3 and mGlu5 receptors: potential targets for novel antidepressants.

Major depressive disorder is among the most prevalent forms of mental illness. All currently available antidepressant medications have stemmed from study of the mechanisms of serendipitously discovered drugs, and only 30-50% of patients exhibit remission and frequently at least 3-4 weeks are required for manifestation of significant therapeutic effects. To overcome these drawbacks, discovering novel neuronal mechanisms of pathophysiology of depression as well as more effective treatments are necessary.

Epigenetic modifications of GABAergic interneurons are associated with the schizophrenia-like phenotype induced by prenatal stress in mice.

Human studies suggest that a variety of prenatal stressors are related to high risk for cognitive and behavioral abnormalities associated with psychiatric illness (Markham and Koenig, 2011). Recently, a downregulation in the expression of GABAergic genes (i.e.

Pharmacological activation of group-II metabotropic glutamate receptors corrects a schizophrenia-like phenotype induced by prenatal stress in mice.

Prenatal exposure to restraint stress causes long-lasting changes in neuroplasticity that likely reflect pathological modifications triggered by early-life stress. We found that the offspring of dams exposed to repeated episodes of restraint stress during pregnancy (here named 'prenatal restraint stress mice' or 'PRS mice') developed a schizophrenia-like phenotype, characterized by a decreased expression of brain-derived neurotrophic factor and glutamic acid decarboxylase 67, an increased expression of type-1 DNA methyl transferase (DNMT1) in the frontal cortex, and a deficit in social interaction, locomotor activity, and prepulse inhibition. PRS mice also showed a marked decrease in metabotropic glutamate 2 (mGlu2) and mGlu3 receptor mRNA and protein levels in the frontal cortex, which was manifested at birth and persisted in adult life.

Growth arrest and DNA-damage-inducible, beta (GADD45b)-mediated DNA demethylation in major psychosis.

Aberrant neocortical DNA methylation has been suggested to be a pathophysiological contributor to psychotic disorders. Recently, a growth arrest and DNA-damage-inducible, beta (GADD45b) protein-coordinated DNA demethylation pathway, utilizing cytidine deaminases and thymidine glycosylases, has been identified in the brain. We measured expression of several members of this pathway in parietal cortical samples from the Stanley Foundation Neuropathology Consortium (SFNC) cohort.

Activation of group II metabotropic glutamate receptors promotes DNA demethylation in the mouse brain.

Activation of group II metabotropic glutamate receptors (mGlu2 and -3 receptors) has shown a potential antipsychotic activity, yet the underlying mechanism is only partially known. Altered epigenetic mechanisms contribute to the pathogenesis of schizophrenia and currently used medications exert chromatin remodeling effects. Here, we show that systemic injection of the brain-permeant mGlu2/3 receptor agonist (-)-2-oxa-4-aminobicyclo[3.

Induction of the Wnt antagonist Dickkopf-1 is involved in stress-induced hippocampal damage.

The identification of mechanisms that mediate stress-induced hippocampal damage may shed new light into the pathophysiology of depressive disorders and provide new targets for therapeutic intervention. We focused on the secreted glycoprotein Dickkopf-1 (Dkk-1), an inhibitor of the canonical Wnt pathway, involved in neurodegeneration. Mice exposed to mild restraint stress showed increased hippocampal levels of Dkk-1 and reduced expression of β-catenin, an intracellular protein positively regulated by the canonical Wnt signalling pathway.

Repeated anabolic androgenic steroid treatment causes antidepressant-reversible alterations of the hypothalamic-pituitary-adrenal axis, BDNF levels and behavior.

Abuse of anabolic androgenic steroids (AASs) is frequently associated with changes in mood, including depression. However, the nature of this association is still largely unexplored. As a model of AAS abuse, we used male adult rats injected for 4 weeks with either nandrolone or stanozolol at daily doses (5 mg/kg, s.

Simultaneous analysis of diazepam and its metabolites in rat plasma and brain tissue by HPLC-UV and SPE.

Diazepam is frequently used as an adjuvant during antidepressant therapy. Recently, some studies have suggested that the treatment with benzodiazepines could have different efficacy in depressed patients as opposed to non-depressed ones. To clarify the matter, a study is currently underway, regarding the drug metabolism in rats.

Changes in BDNF serum levels in patients with major depression disorder (MDD) after 6 months treatment with sertraline, escitalopram, or venlafaxine.

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.