Funda Orhan

Skeletal Muscle PGC-1α1 Modulates Kynurenine Metabolism and Mediates Resilience to Stress-Induced Depression

Depression is a debilitating condition with a profound impact on quality of life for millions of people worldwide. Physical exercise is used as a treatment strategy for many patients, but the mechanisms that underlie its beneficial effects remain unknown. Here, we describe a mechanism by which skeletal muscle PGC-1α1 induced by exercise training changes kynurenine metabolism and protects from stress-induced depression. Activation of the PGC-1α1-PPARα/δ pathway increases skeletal muscle expression of kynurenine aminotransferases, thus enhancing the conversion of kynurenine into kynurenic acid, a metabolite unable to cross the blood-brain barrier. Reducing plasma kynurenine protects the brain from stress-induced changes associated with depression and renders skeletal muscle-specific PGC-1α1 transgenic mice resistant to depression induced by chronic mild stress or direct kynurenine administration. This study opens therapeutic avenues for the treatment of depression by targeting the PGC-1α1-PPAR axis in skeletal muscle, without the need to cross the blood-brain barrier.

Lower levels of the glial cell marker TSPO in drug-naive first-episode psychosis patients as measured using PET and |[lsqb]|11C|[rsqb]|PBR28

Several lines of evidence are indicative of a role for immune activation in the pathophysiology of schizophrenia. Nevertheless, studies using positron emission tomography (PET) and radioligands for the translocator protein (TSPO), a marker for glial activation, have yielded inconsistent results. Whereas early studies using a radioligand with low signal-to-noise in small samples showed increases in patients, more recent studies with improved methodology have shown no differences or trend-level decreases. Importantly, all patients investigated thus far have been on antipsychotic medication, and as these compounds may dampen immune cell activity, this factor limits the conclusions that can be drawn. Here, we examined 16 drug-naive, first-episode psychosis patients and 16 healthy controls using PET and the TSPO radioligand [11C]PBR28. Gray matter (GM) volume of distribution (VT) derived from a two-tissue compartmental analysis with arterial input function was the main outcome measure. Statistical analyses were performed controlling for both TSPO genotype, which is known to affect [11C]PBR28 binding, and gender. There was a significant reduction of [11C]PBR28 VT in patients compared with healthy controls in GM as well as in secondary regions of interest. No correlation was observed between GM VT and clinical or cognitive measures after correction for multiple comparisons. The observed decrease in TSPO binding suggests reduced numbers or altered function of immune cells in brain in early-stage schizophrenia.

Behavioral disturbances in adult mice following neonatal virus infection or kynurenine treatment – Role of brain kynurenic acid

Exposure to infections in early life is considered a risk-factor for developing schizophrenia. Recently we reported that a neonatal CNS infection with influenza A virus in mice resulted in a transient induction of the brain kynurenine pathway, and subsequent behavioral disturbances in immune-deficient adult mice. The aim of the present study was to investigate a potential role in this regard of kynurenic acid (KYNA), an endogenous antagonist at the glycine site of the N-methyl-D-aspartic acid (NMDA) receptor and at the cholinergic α7 nicotinic receptor. C57BL/6 mice were injected i.p. with neurotropic influenza A/WSN/33 virus (2400 plaque-forming units) at postnatal day (P) 3 or with L-kynurenine (2×200 mg/kg/day) at P7-16. In mice neonatally treated with L-kynurenine prepulse inhibition of the acoustic startle, anxiety, and learning and memory were also assessed. Neonatally infected mice showed enhanced sensitivity to D-amphetamine-induced (5 mg/kg i.p.) increase in locomotor activity as adults. Neonatally L-kynurenine treated mice showed enhanced sensitivity to D-amphetamine-induced (5 mg/kg i.p.) increase in locomotor activity as well as mild impairments in prepulse inhibition and memory. Also, D-amphetamine tended to potentiate dopamine release in the striatum in kynurenine-treated mice. These long-lasting behavioral and neurochemical alterations suggest that the kynurenine pathway can link early-life infection with the development of neuropsychiatric disturbances in adulthood.

CSF GABA is reduced in first-episode psychosis and associates to symptom severity

Schizophrenia is characterized by a multiplicity of symptoms arising from almost all domains of mental function. γ-Aminobutyric acid (GABA) is the primary inhibitory neurotransmitter in the brain and is increasingly recognized to have a significant role in the pathophysiology of the disorder. In the present study, cerebrospinal fluid (CSF) concentrations of GABA were analyzed in 41 first-episode psychosis (FEP) patients and 21 age- and sex-matched healthy volunteers by high-performance liquid chromatography. We found lower CSF GABA concentration in FEP patients compared with that in the healthy volunteers, a condition that was unrelated to antipsychotic and/or anxiolytic medication. Moreover, lower CSF GABA levels were associated with total and general score of Positive and Negative Syndrome Scale, illness severity and probably with a poor performance in a test of attention. This study offers clinical in vivo evidence for a potential role of GABA in early-stage schizophrenia.

Kynurenic Acid levels in cerebrospinal fluid from patients with Alzheimer's disease or dementia with lewy bodies.

Kynurenic acid (KYNA) is implicated in cognitive functions. Altered concentrations of the compound are found in serum and cerebrospinal fluid (CSF) of patients with Alzheimers disease (AD). Further studies to determine whether KYNA serves as a biomarker for cognitive decline and dementia progression are required. In this study, we measured CSF KYNA levels in AD patients (n = 19), patients with dementia with Lewy bodies (DLB) (n = 18), and healthy age-matched controls (Ctrls)) (n = 20) to further explore possible correlations between KYNA levels, cognitive decline, and well-established AD and inflammatory markers. Neither DLB patients nor AD patients showed significantly altered CSF KYNA levels compared to Ctrls. However, female AD patients displayed significantly higher KYNA levels compared to male AD patients, a gender difference not seen in the Ctrl or DLB group. Levels of KYNA significantly correlated with the AD-biomarker P-tau and the inflammation marker soluble intercellular adhesion molecule-1 (sICAM-1) in the AD patient group. No associations between KYNA and cognitive functions were found. Our study shows that, although KYNA was not associated with cognitive decline in AD or DLB patients, it may be implicated in AD-related hyperphosphorylation of tau and inflammation. Further studies on larger patient cohorts are required to understand the potential role of KYNA in AD and DLB.

Positive symptoms associate with cortical thinning in the superior temporal gyrus via the ENIGMA Schizophrenia consortium

Based on the role of the superior temporal gyrus (STG) in auditory processing, language comprehension and self‐monitoring, this study aimed to investigate the relationship between STG cortical thickness and positive symptom severity in schizophrenia.

Tryptophan metabolism along the kynurenine pathway downstream of toll‐like receptor stimulation in peripheral monocytes

Tryptophan degradation along the kynurenine pathway is of central importance for the immune function. Toll‐like receptors (TLRs), representing the first line of immune defence against pathogens, are expressed in various cell types. The most abundant expression is found on monocytes, macrophages and dendritic cells. The aim of this study was to investigate whether stimulation with different TLR ligands induces the kynurenine pathway in human peripheral monocytes. Cell supernatants were analysed using a liquid chromatography/mass spectrometry to measure kynurenine, kynurenic acid (KYNA), quinolinic acid (QUIN) and tryptophan. Stimulation of TLR‐2, TLR‐3, TLR‐4, TLR‐7/8 and TLR‐9 was found to induce the production of kynurenine, but only stimulation of TLR‐3 increased levels of further downstream metabolites, such as KYNA and QUIN. Stimulation of TLR‐1, TLR‐5 and TLR‐6 did not induce the kynurenine pathway. Taken together, this study provides novel evidence demonstrating that TLR activation induces a pattern of downstream tryptophan degradation along the kynurenine pathway in monocytes. The results of this study may implicate that TLRs can be used as new drug targets for the regulation of aberrant tryptophan metabolism along this pathway, a potential therapeutic strategy that may be of importance in several disorders.

Cerebrospinal fluid levels of sphingolipids associate with disease severity in first episode psychosis patients

Alterations in brain lipid composition have been described in schizophrenia (Hamazaki et al., 2015; Schmitt et al., 2004; Amminger et al., 2012), a disease characterized by positive and negative symptoms as well as with deficits in cognitive function (Fatouros-Bergman et al., 2014). Specifically, decreased levels of sphingomyelins and hexosylceramides in thalamus (Schmitt et al., 2004) and reduced gene expression of the sphingolipid pathway in prefrontal cortical samples (Narayan et al., 2009) have been described, as well as an association between sphingomyelin levels in red blood cell (RBC) membranes and symptom severity (Tessier et al., 2016). Sphingomyelins and hexosylceramides (Supplemental Material) are sphingolipids that possess structural as well as signaling functions in the brain. In a previous study (Checa et al., 2015), we found increased levels of HexCer24:1 in the cerebrospinalfluid (CSF) of patientswith schizophrenia,who served as part of the disease control group. This led us to hypothesize that the observed alterations may form part of pathophysiological mechanisms of the disease. Using liquid chromatography tandemmass spectrometry (Supplementary Material) we measured CSF levels of HexCer24:1 in cohortswith first episode psychosis (FEP) patients, chronic schizophrenia, or schizoaffective disorder. Levels of other hexosylceramides and sphingomyelins were measured as an exploratory aim. FEP patients (n = 44) were recruited within the Karolinska Schizophrenia Project (Orhan et al., 2017), whereas chronic patients (n = 23) were included from Linköping (Skogh et al., 2011). Twenty-five of 44 FEP patientswere drug naïve to antipsychoticmedication. Psychotic symptoms and global functioningwere assessed andmeasuredwith Positive and Negative Syndrome Scale (PANSS), Global Assessment of Functioning (GAF) and Clinical Global Impression (CGI). In the FEP cohort, patients on antipsychotic medication presented lower GAF symptoms scores relative to drug-naïve patients (p= 0.026) and higher CGI scores (p = 0.077), indicating a more severe stage of the disease (Supplementary Material). All chronic patients were on treatment with oral olanzapine. Sphingolipids from two control groups of healthy volunteers, age-matched with FEP patients and patients with chronic schizophrenia were analyzed (n= 20 and n= 10, respectively). CSF levels of sphingolipids did not differ between FEP patients and healthy controls or between chronic patients and healthy controls (Table 1). Amongst FEP patients, the levels of HexCer24:1 (p = 0.011) were higher in patients that had received antipsychotic treatment

Increased number of monocytes and plasma levels of MCP-1 and YKL-40 in first-episode psychosis

Accumulating evidence implicates immune activation in the development of schizophrenia. Here, monocyte numbers, monocyte chemoattractant protein‐1 (MCP‐1) and chitinase‐3‐like protein 1 (YKL‐40) were investigated in plasma and cerebrospinal fluid (CSF) in first‐episode psychosis (FEP) patients.