Altered cortical synaptic lipid signaling leads to intermediate phenotypes of mental disorders.

Excitation/inhibition (E/I) balance plays important roles in mental disorders. Bioactive phospholipids like lysophosphatidic acid (LPA) are synthesized by the enzyme autotaxin (ATX) at cortical synapses and modulate glutamatergic transmission, and eventually alter E/I balance of cortical networks. Here, we analyzed functional consequences of altered E/I balance in 25 human subjects induced by genetic disruption of the synaptic lipid signaling modifier PRG-1, which were compared to 25 age and sex matched control subjects. Furthermore, we tested therapeutic options targeting ATX in a related mouse line. Using EEG combined with TMS in an instructed fear paradigm, neuropsychological analysis and an fMRI based episodic memory task, we found intermediate phenotypes of mental disorders in human carriers of a loss-of-function single nucleotide polymorphism of PRG-1 (PRG-1R345T/WT). Prg-1R346T/WT animals phenocopied human carriers showing increased anxiety, a depressive phenotype and lower stress resilience. Network analysis revealed that coherence and phase-amplitude coupling were altered by PRG-1 deficiency in memory related circuits in humans and mice alike. Brain oscillation phenotypes were restored by inhibtion of ATX in Prg-1 deficient mice indicating an interventional potential for mental disorders.

Reduced NLRP3 Gene Expression Limits the IL-1ß Cleavage via Inflammasome in Monocytes from Severely Injured Trauma Patients.

OBJECTIVE: Traumatic injury or severe surgery leads to a profound immune response with a diminished functionality of monocytes and subsequently their IL-1ß release. IL-1ß plays an important role in host immunity and protection against infections. Its biological activation via IL-1ß-precursor processing requires the transcription of inflammasome components and their activation. Deregulated activity of NOD-like receptor inflammasomes (NLR) like NLRP3 that leads to the maturation of IL-1ß has been described in various diseases. While the role of other inflammasomes has been studied in monocytes, nothing is known about NLRP3 inflammasome after a traumatic injury. Here, the role of the NLRP3 inflammasome in impaired monocyte functionality after a traumatic injury was analyzed. MEASUREMENTS AND MAIN RESULTS: Ex vivo-in vitro stimulation of isolated CD14+ monocytes with lipopolysaccharide (LPS) showed a significantly higher IL-1ß secretion in healthy volunteers (HV) compared to trauma patients (TP) after admission. Reduced IL-1ß secretion was paralleled by significantly lowered gene expression of NLRP3 in monocytes from TP compared to those of HV. Transfection of monocytes with NLRP3-encoding plasmid recovered the functionality of monocytes from TP regarding the IL-1ß secretion. CONCLUSIONS: This study demonstrates that CD14+ monocytes from TP are significantly diminished in their function and that the presence of NLRP3 components is necessary in recovering the ability of monocytes to produce active IL-1ß. This recovery of the NLRP3 inflammasome in monocytes may imply a new target for treatment and therapy of immune suppression after severe injury.

Traumatic Injury.

Traumatic injury as one of the world's most relevant but neglected health concerns results in modulated inflammasome activity, which is closely linked to the development of post-injury complications. Cytokine-producing capacity of cells is important for the appropriate immune response to trauma and requires not only synthesis and transcription of inflammasome components but also their activation. Unfortunately, the precise role of inflammasome in trauma is still largely unknown. However, in the following chapter, we provide an overview on the best described inflammasomes in the various settings of trauma, introducing the recent findings on the up-to-date best described NLRP inflammasomes and underlying cytokines in the inflammatory response to trauma.

Excitability regulation in the dorsomedial prefrontal cortex during sustained instructed fear responses: a TMS-EEG study.

Threat detection is essential for protecting individuals from adverse situations, in which a network of amygdala, limbic regions and dorsomedial prefrontal cortex (dmPFC) regions are involved in fear processing. Excitability regulation in the dmPFC might be crucial for fear processing, while abnormal patterns could lead to mental illness. Notwithstanding, non-invasive paradigms to measure excitability regulation during fear processing in humans are missing. To address this challenge we adapted an approach for excitability characterization, combining electroencephalography (EEG) and transcranial magnetic stimulation (TMS) over the dmPFC during an instructed fear paradigm, to dynamically dissect its role in fear processing. Event-related (ERP) and TMS-evoked potentials (TEP) were analyzed to trace dmPFC excitability. We further linked the excitability regulation patterns to individual MRI-derived gray matter structural integrity of the fear network. Increased cortical excitability was demonstrated to threat (T) processing in comparison to no-threat (NT), reflected by increased amplitude of evoked potentials. Furthermore, TMS at dmPFC enhanced the evoked responses during T processing, while the structural integrity of the dmPFC and amygdala predicted the excitability regulation patterns to fear processing. The dmPFC takes a special role during fear processing by dynamically regulating excitability. The applied paradigm can be used to non-invasively track response abnormalities to threat stimuli in healthy subjects or patients with mental disorders.

Adrenergic stimulation alters the expression of inflammasome components and interleukins in primary human monocytes.

Prior to their release, interleukin (IL)-1ß and IL-18 are cleaved to their bioactive forms by a multiprotein complex known as an inflammasome, which is comprised of a number of elements that are subject to nuclear factor-κB-dependent transcription. Catecholamines have been indicated to exert an enhancing effect on the IL-1ß release. The aim of the present study was to determine whether alterations in inflammasome gene expression may be responsible for the modified IL-1ß and IL-18 secretion following lipopolysaccharide (LPS) and catecholamine co-stimulation. Monocytes were isolated from the peripheral blood of 21 healthy volunteers using CD14+ microbeads. Following stimulation with LPS (2 µg/ml) and/or phenylephrine (PE; 10 µM) for 24 h, the supernatants were subjected to ELISA to evaluate the ex vivo protein expression levels of IL-1ß and IL-18. In addition, the gene expression levels of inflammasome components associated with the cleavage of IL-1ß and IL-18, including NLRP1, NLRP3, caspase-1 and PYCARD were determined using polymerase chain reaction. The results indicated that LPS significantly increased IL-1ß expression compared with the unstimulated control samples. Co-stimulation with LPS + PE significantly enhanced IL-1ß expression compared with LPS alone. Furthermore, IL-18 expression was significantly reduced by LPS and LPS + PE co-stimulation. The gene expression levels of IL-18, NLRP1, caspase-1 and PYCARD were comparable in the LPS- and LPS + PE-stimulated cells. LPS significantly induced the expression levels of IL-1ß and NLRP3, and to a lesser degree, the expression of NLRP1, compared with the control. By contrast, PE markedly induced the expression levels of IL-18 and NLRP1, while LPS reduced the gene expression of IL-18. In conclusion, adrenergic stimulation suppressed NLRP3 expression and enhanced NLRP1 expression, indicating that NLRP3 may regulate IL-1ß secretion and NLRP1 may regulate the release of IL-18.