scholarly journals Dysregulation of kynurenine metabolism is related to proinflammatory cytokines, attention, and prefrontal cortex volume in schizophrenia

2019 ◽  
Vol 25 (11) ◽  
pp. 2860-2872 ◽  
Author(s):  
Jochen Kindler ◽  
Chai K. Lim ◽  
Cynthia Shannon Weickert ◽  
Danny Boerrigter ◽  
Cherrie Galletly ◽  
...  
Keyword(s):  
Prefrontal Cortex ◽  
Proinflammatory Cytokines ◽  
Kynurenine Pathway ◽  
Enzyme Synthesis ◽  
Postmortem Brain ◽  
Mrna Levels ◽  
Brain Volumes ◽  
Immune System Activation ◽  
Tryptophan Dioxygenase ◽  
Dorsolateral Prefrontal

Abstract The kynurenine pathway (KP) of tryptophan (TRP) catabolism links immune system activation with neurotransmitter signaling. The KP metabolite kynurenic acid (KYNA) is increased in the brains of people with schizophrenia. We tested the extent to which: (1) brain KP enzyme mRNAs, (2) brain KP metabolites, and (3) plasma KP metabolites differed on the basis of elevated cytokines in schizophrenia vs. control groups and the extent to which plasma KP metabolites were associated with cognition and brain volume in patients displaying elevated peripheral cytokines. KP enzyme mRNAs and metabolites were assayed in two independent postmortem brain samples from a total of 71 patients with schizophrenia and 72 controls. Plasma KP metabolites, cognition, and brain volumes were measured in an independent cohort of 96 patients with schizophrenia and 81 healthy controls. Groups were stratified based on elevated vs. normal proinflammatory cytokine mRNA levels. In the prefrontal cortex (PFC), kynurenine (KYN)/TRP ratio, KYNA levels, and mRNA for enzymes, tryptophan dioxygenase (TDO) and kynurenine aminotransferases (KATI/II), were significantly increased in the high cytokine schizophrenia subgroup. KAT mRNAs significantly correlated with mRNA for glial fibrillary acidic protein in patients. In plasma, the high cytokine schizophrenia subgroup displayed an elevated KYN/TRP ratio, which correlated inversely with attention and dorsolateral prefrontal cortex (DLPFC) volume. This study provides further evidence for the role of inflammation in a subgroup of patients with schizophrenia and suggests a molecular mechanism through which inflammation could lead to schizophrenia. Proinflammatory cytokines may elicit conversion of TRP to KYN in the periphery and increase the N-methyl-d-aspartate receptor antagonist KYNA via increased KAT mRNA and possibly more enzyme synthesis activity in brain astrocytes,  leading to DLPFC volume loss, and attention impairment in schizophrenia.

scholarly journals Changes in Self-reported Energy and Brain Volumes

2020 ◽  
Vol 4 (Supplement_1) ◽  
pp. 783-783
Author(s):  
Qu Tian ◽  
Andrea Rosso ◽  
Nancy Glynn ◽  
Xiaonan Zhu ◽  
Caterina Rosano
Keyword(s):  
Prefrontal Cortex ◽  
Mixed Models ◽  
Rate Of Change ◽  
Self Report ◽  
Precentral Gyrus ◽  
Brain Health ◽  
Brain Volumes ◽  
The Past ◽  
Dorsolateral Prefrontal ◽  
The Brain

Abstract The brain demands and consumes more energy than any other organ. Lower perceived energy may indicate compromised brain health. Little empirical data exists on the association between perceived energy and brain structure. Neuroimaging was obtained in 300 participants (mean age=83±3 y/o, 40% blacks, 57%women) with repeated self-reported energy measures(scale0-10) in the past decade. Energy decline was computed as rate of change by linear mixed models(-0.06/year). Associations of energy decline with volumes of cognitive (dorsolateral prefrontal cortex, hippocampus) and motor (precentral gyrus, putamen, caudate) areas were examined using linear regression, adjusted for demographics and total gray matter atrophy. A steeper decline in energy was associated with smaller volumes of right putamen (p=0.013) and caudate (p=0.043), a trend in right precentral gyrus (p=0.085), but not in prefrontal cortex or hippocampus. Declining energy by self-report may indicate atrophy localized in subcortical motor areas. Studies to identify the mechanisms underlying these associations are warranted.

scholarly journals IL-37 is increased in brains of children with autism spectrum disorder and inhibits human microglia stimulated by neurotensin

2019 ◽  
Vol 116 (43) ◽  
pp. 21659-21665 ◽  
Author(s):  
Irene Tsilioni ◽  
Arti B. Patel ◽  
Harry Pantazopoulos ◽  
Sabina Berretta ◽  
Pio Conti ◽  
...  
Keyword(s):  
Gene Expression ◽  
Autism Spectrum Disorder ◽  
Prefrontal Cortex ◽  
Proinflammatory Cytokines ◽  
Dorsolateral Prefrontal Cortex ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Human Microglia ◽  
Children With Asd ◽  
Dorsolateral Prefrontal

Autism spectrum disorder (ASD) does not have a distinct pathogenesis or effective treatment. Increasing evidence supports the presence of immune dysfunction and inflammation in the brains of children with ASD. In this report, we present data that gene expression of the antiinflammatory cytokine IL-37, as well as of the proinflammatory cytokines IL-18 and TNF, is increased in the amygdala and dorsolateral prefrontal cortex of children with ASD as compared to non-ASD controls. Gene expression of IL-18R, which is a receptor for both IL-18 and IL-37, is also increased in the same brain areas of children with ASD. Interestingly, gene expression of the NTR3/sortilin receptor is reduced in the amygdala and dorsolateral prefrontal cortex. Pretreatment of cultured human microglia from normal adult brains with human recombinant IL-37 (1 to 100 ng/mL) inhibits neurotensin (NT)-stimulated secretion and gene expression of IL-1β and CXCL8. Another key finding is that NT, as well as the proinflammatory cytokines IL-1β and TNF increase IL-37 gene expression in cultured human microglia. The data presented here highlight the connection between inflammation and ASD, supporting the development of IL-37 as a potential therapeutic agent of ASD.

Reduced GSK-3? mRNA levels in postmortem dorsolateral prefrontal cortex of schizophrenic patients

2004 ◽  
Vol 111 (12) ◽  
pp. 1583-1592 ◽  
Author(s):  
N. Kozlovsky ◽  
C. Shanon-Weickert ◽  
E. Tomaskovic-Crook ◽  
J. E. Kleinman ◽  
R. H. Belmaker ◽  
...  
Keyword(s):  
Prefrontal Cortex ◽  
Dorsolateral Prefrontal Cortex ◽  
Mrna Levels ◽  
Dorsolateral Prefrontal ◽  
Schizophrenic Patients

scholarly journals Concordance of Immune-Related Markers in Lymphocytes and Prefrontal Cortex in Schizophrenia

2021 ◽  
Vol 2 (1) ◽  
Author(s):  
Eleonora Gatta ◽  
Vikram Saudagar ◽  
Jenny Drnevich ◽  
Marc P Forrest ◽  
James Auta ◽  
...  
Keyword(s):  
Prefrontal Cortex ◽  
Rna Sequencing ◽  
Inflammatory Responses ◽  
Expression Profiles ◽  
Quantitative Polymerase Chain Reaction ◽  
Synaptic Function ◽  
Differentially Expressed ◽  
Postmortem Brain ◽  
Mrna Levels ◽  
Biological Processes

Abstract Schizophrenia is a severe neuropsychiatric disorder associated with a wide array of transcriptomic and neurobiochemical changes. Genome-wide transcriptomic profiling conducted in postmortem brain have provided novel insights into the pathophysiology of this disorder, and identified biological processes including immune/inflammatory-related responses, metabolic, endocrine, and synaptic function. However, few studies have investigated whether similar changes are present in peripheral tissue. Here, we used RNA-sequencing to characterize transcriptomic profiles of lymphocytes in 18 nonpsychotic controls and 19 individuals with schizophrenia. We identified 2819 differentially expressed transcripts (Pnominal < .05) in the schizophrenia group when compared to controls. Bioinformatic analyses conducted on a subset of 293 genes (Pnominal < .01 and |log2 FC| > 0.5) highlighted immune/inflammatory responses as key biological processes in our dataset. Differentially expressed genes in lymphocytes were highly enriched in gene expression profiles associated with cortex layer 5a and immune cells. Thus, we investigated whether the changes in transcripts levels observed in lymphocytes could also be detected in the prefrontal cortex (PFC, BA10) in a second replication cohort of schizophrenia subjects. Remarkably, mRNA levels detected in the PFC and lymphocytes were in strong agreement, and measurements obtained using RNA-sequencing positively correlated with data obtained by reverse transcriptase-quantitative polymerase chain reaction analysis. Collectively, our work supports a role for immune dysfunction in the pathogenesis of schizophrenia and suggests that peripheral markers can be used as accessible surrogates to investigate putative central nervous system disruptions.

Endocannabinoid system imbalance in the postmortem prefrontal cortex of subjects with schizophrenia

2019 ◽  
Vol 33 (9) ◽  
pp. 1132-1140 ◽  
Author(s):  
Carolina Muguruza ◽  
Benito Morentin ◽  
J Javier Meana ◽  
Stephen PH Alexander ◽  
Luis F Callado
Keyword(s):  
Prefrontal Cortex ◽  
Cannabinoid Receptors ◽  
Fatty Acid Amide Hydrolase ◽  
Acid Amide ◽  
Endocannabinoid System ◽  
Postmortem Brain ◽  
Functional Coupling ◽  
Mrna Levels ◽  
The Status ◽  
And Function

Background: The endocannabinoid system – comprising cannabinoid receptors, endocannabinoid ligands and their synthesis and inactivation enzymes – has been widely implicated in the pathophysiology of schizophrenia. However, little is known regarding the status of the different elements of the endocannabinoid system in the brain of schizophrenic patients. We have previously reported altered endocannabinoid levels in the postmortem brain of subjects with schizophrenia compared with matched controls. Aims: Our aim was to further examine the status of the main elements of the endocannabinoid system in the postmortem prefrontal cortex of the same cohort of subjects. Methods: Gene expression and function of the cannabinoid receptor type-1 (CB1) and the endocannabinoid degrading enzymes fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) have been assessed. Results: A significant decrease in CB1 mRNA levels in schizophrenia was found, without alteration of FAAH or MAGL mRNA expression. Moreover, positive correlations among mRNA expressions of the three genes studied were found in the prefrontal cortex of controls but not in schizophrenic subjects. No alteration was found in CB1 receptor mediated functional coupling to G-proteins, but a significant increase of FAAH activity was found in schizophrenic subjects compared with controls. 2-arachidonoylglycerol levels and MAGL activity were found to positively correlate in controls but not in schizophrenic subjects. Conclusions: The present findings reveal an imbalance in the expression and function of different elements of the endocannabinoid system in schizophrenia. This outcome highlights the relevance of the endocannabinoid system in the pathophysiology of schizophrenia and emphasises its elements as potential targets in the search for new therapeutic strategies.

scholarly journals Glycosylation enzyme mRNA expression in dorsolateral prefrontal cortex of elderly patients with schizophrenia: Evidence for dysregulation of multiple glycosylation pathways

2018 ◽  
Author(s):  
Toni M. Mueller ◽  
Micah S. Simmons ◽  
Ashley T. Helix ◽  
Vahram Haroutunian ◽  
James H. Meador-Woodruff
Keyword(s):  
Prefrontal Cortex ◽  
Dorsolateral Prefrontal Cortex ◽  
Sphingolipid Metabolism ◽  
Common Mechanism ◽  
Transcript Expression ◽  
Mrna Levels ◽  
Enzyme Expression ◽  
Comparison Subject ◽  
Dorsolateral Prefrontal ◽  
Qpcr Array

Altered protein post-translational modifications such as glycosylation have become a target of investigation in the pathophysiology of schizophrenia. Disrupted glycosylation associated processes including atypical sphingolipid metabolism, reduced polysialylation of cell adhesion molecules, abnormal proteoglycan expression, and irregular glycan synthesis and branching have also been reported in this disorder. These pathways are regulated by the expression of glycosidases and glycosyltransferases, classes of enzymes which comprise approximately 2% of the genome. Many glycosylation enzymes can participate in multiple glycosylation pathways and dysregulation of enzyme expression could represent a common mechanism leading to a variety of glycan processing deficits in schizophrenia. In matched pairs of elderly schizophrenia and comparison subject (N = 12 pairs) dorsolateral prefrontal cortex, we measured mRNA levels of 84 key glycosylation enzymes by qPCR array. We found dysregulated transcript expression of 36 glycosylation enzymes from 12 functional categories. All of the abnormally expressed enzymes demonstrated increased transcript expression in schizophrenia, and many altered enzymes are known to modify substrates that have been previously implicated in the pathophysiology this illness. These findings suggest that abnormal glycosylation enzyme expression in schizophrenia may contribute to dysregulation of multiple glycosylation pathways, and disruptions of these central cell signaling processes may underlie a variety of deficits in schizophrenia.

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