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The GluN2A subunit of NMDA receptors (NMDARs) plays a critical role during postnatal brain development as its expression increases while Glun2B expression decreases. Mutations and polymorphisms in GRIN2A gene, coding for GluN2A, are linked to developmental brain disorders such as mental retardation, epilepsy, schizophrenia. Published data suggest that GluN2A is involved in maturation and phenotypic maintenance of parvalbumin interneurons (PVIs), and these interneurons suffer from a deficient glutamatergic neurotransmission via GluN2A-containing NMDARs in schizophrenia. In the present study, we find that although PVIs and their associated perineuronal nets (PNNs) appear normal in anterior cingulate cortex of late adolescent/young adult GRIN2A KO mice, a lack of GluN2A delays PNN maturation. GRIN2A KO mice display a susceptibility to redox dysregulation as sub-threshold oxidative stress and subtle alterations in antioxidant systems are observed in their prefrontal cortex. Consequently, an oxidative insult applied during early postnatal development increases oxidative stress, decreases the number of parvalbumin-immunoreactive cells, and weakens the PNNs in KO but not WT mice. These effects are long-lasting, but preventable by the antioxidant, N-acetylcysteine. The persisting oxidative stress, deficit in PVIs and PNNs, and reduced local high-frequency neuronal synchrony in anterior cingulate of late adolescent/young adult KO mice, which have been challenged by an early-life oxidative insult, is accompanied with microglia activation. Altogether, these indicate that a lack of GluN2A-containing NMDARs alters the fine control of redox status, leading to a delayed maturation of PNNs, and conferring vulnerability for long-term oxidative stress, microglial activation, and PVI network dysfunction.

Biomarker-guided treatments are needed in psychiatry, and previous data suggest oxidative stress may be a target in schizophrenia. A previous add-on trial with the antioxidant N-acetylcysteine (NAC) led to negative symptom reductions in chronic patients. We aim to study NAC’s impact on symptoms and neurocognition in early psychosis (EP) and to explore whether glutathione (GSH)/redox markers could represent valid biomarkers to guide treatment. In a double-blind, randomized, placebo-controlled trial in 63 EP patients, we assessed the effect of NAC supplementation (2700 mg/day, 6 months) on PANSS, neurocognition, and redox markers (brain GSH [GSHmPFC], blood cells GSH levels [GSHBC], GSH peroxidase activity [GPxBC]). No changes in negative or positive symptoms or functional outcome were observed with NAC, but significant improvements were found in favor of NAC on neurocognition (processing speed). NAC also led to increases of GSHmPFC by 23% (P = .005) and GSHBC by 19% (P = .05). In patients with high-baseline GPxBC compared to low-baseline GPxBC, subgroup explorations revealed a link between changes of positive symptoms and changes of redox status with NAC. In conclusion, NAC supplementation in a limited sample of EP patients did not improve negative symptoms, which were at modest baseline levels. However, NAC led to some neurocognitive improvements and an increase in brain GSH levels, indicating good target engagement. Blood GPx activity, a redox peripheral index associated with brain GSH levels, could help identify a subgroup of patients who improve their positive symptoms with NAC. Thus, future trials with antioxidants in EP should consider biomarker-guided treatment.

Recent studies implicate the arginine-decarboxylation product agmatine in mood regulation. Agmatine has antidepressant properties in rodent models of depression, and agmatinase (Agmat), the agmatine-degrading enzyme, is upregulated in the brains of mood disorder patients. We have previously shown that mice lacking CREB-regulated transcription coactivator 1 (CRTC1) associate behavioral and molecular depressive-like endophenotypes, as well as blunted responses to classical antidepressants. Here, the molecular basis of the behavioral phenotype of Crtc1−/− mice was further examined using microarray gene expression profiling that revealed an upregulation of Agmat in the cortex of Crtc1−/− mice. Quantitative polymerase chain reaction and western blot analyses confirmed Agmat upregulation in the Crtc1−/− prefrontal cortex (PFC) and hippocampus, which were further demonstrated by confocal immunofluorescence microscopy to comprise an increased number of Agmat-expressing cells, notably parvalbumin- and somatostatin-positive interneurons. Acute agmatine and ketamine treatments comparably improved the depressive-like behavior of male and female Crtc1−/− mice in the forced swim test, suggesting that exogenous agmatine has a rapid antidepressant effect through the compensation of agmatine deficit because of upregulated Agmat. Agmatine rapidly increased brain-derived neurotrophic factor (BDNF) levels only in the PFC of wild-type (WT) females, and decreased eukaryotic elongation factor 2 (eEF2) phosphorylation in the PFC of male and female WT mice, indicating that agmatine might be a fast-acting antidepressant with N-methyl-D-aspartate (NMDA) receptor antagonist properties. Collectively, these findings implicate Agmat in the depressive-like phenotype of Crtc1−/− mice, refine current understanding of the agmatinergic system in the brain and highlight its putative role in major depression.

Extracellular glutamate levels were measured by microdialysis in the prefrontal cortex (PFC) of anaesthetised rats in response to a short, experimenter-provoked mechanical movement of the animal head. Movement caused significant, nerve impulse-independent elevations of glutamate levels (maximum increase, 300+/-30% of baseline). This study reveals a possible artifact in the measurement of extracellular glutamate concentrations by microdialysis and suggests that, in awake animals, treatments associated with stimulation of motor activity can cause non-specific efflux of glutamate in the PFC.

Experimental animals can be differentiated on the basis of their horizontal or vertical activity to high responders (HR) and low responders (LR) upon exposure to a novel environment. These individual differences have been associated with behavioral and neurobiological differences in a number of experimental procedures used for studying sensitivity to psychostimulants, anxiety, depression, and cognitive function. In the present study, we differentiated the rats to HR and LR based on their vertical activity upon exposure to a novel environment. Additionally, we ascertained whether HR and LR rats differ in a battery of tests such as passive avoidance (PA), object recognition (OR), and the water-maze (WM) that provide indices for cognitive function and the forced swim test (FST), an animal model of affective responsivity and antidepressant-like activity. Potential differences in neurochemical indices between the two phenotypes were also examined. HR rats displayed impaired non-spatial object recognition memory, but enhanced spatial performance, as compared to LR rats. FST induced "depressive-like" symptoms in both phenotypes that were differently manifested in HR versus LR rats. Neurochemical findings revealed distinct differences in serotonergic and dopaminergic activity in the striatum and the prefrontal cortex of HR as compared to LR rats. The above results show that HR and LR rats exhibit important differences in a battery of tests related to cognitive performance or affective responsivity, which may be associated with differences in certain neurobiological parameters. Behav Brain Res

SCOPE: Probiotics may influence one-carbon (C1) metabolism, neurotransmitters, liver function markers, or behavior.METHODS AND RESULTS: Male adult Flinders Sensitive Line rats (model of depression, FSL; n = 22) received Lactobacillus helveticus R0052 and Bifidobacterium longum R0175 (109or 1010colony-forming units/d) or vehicle for 10 weeks. The controls, Flinders Resistant Line rats (FRL, n = 8), only received vehicle. C1-related metabolites were measured in plasma, urine, and different tissues. Monoamine concentrations were measured in plasma, hippocampus, and prefrontal cortex. Vehicle-treated FSL rats had higher plasma concentrations of betaine, choline, and dimethylglycine, but lower plasma homocysteine and liver S-adenosylmethionine (SAM) than FRLs. FSL rats receiving high-dose probiotics had lower plasma betaine and higher liver SAM compared to vehicle-treated FSL rats. FSLs had higher concentrations of norepinephrine, dopamine, and serotonin than FRLs across various brain regions. Probiotics decreased plasma dopamine in FSLs in a dose-dependent manner. There were no detectable changes in liver function markers or behavior.CONCLUSIONS: Probiotics reduced the flow of methyl groups via betaine, increased liver SAM, and decreased plasma dopamine and norepinephrine. Since these changes in methylation and catecholamine pathways are known to be involved in several diseases, future investigation of the effect of probiotics is warranted. This article is protected by copyright. All rights reserved.