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Schizophrenia (SZ) and bipolar disorder (BD) share substantial neurodevelopmental components affecting brain maturation and architecture. This necessitates a dynamic lifespan perspective in which brain aberrations are inferred from deviations from expected lifespan trajectories. We applied machine learning to diffusion tensor imaging (DTI) indices of white matter structure and organization to estimate and compare brain age between patients with SZ, patients with BD, and healthy control (HC) subjects across 10 cohorts.

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.

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 VTin patients compared with healthy controls in GM as well as in secondary regions of interest. No correlation was observed between GM VTand 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.

Elevated cerebrospinal fluid (CSF) levels of the glia-derived N-methyl-D-aspartic acid receptor antagonist kynurenic acid (KYNA) have consistently been implicated in schizophrenia and bipolar disorder. Here, we conducted a genome-wide association study based on CSF KYNA in bipolar disorder and found support for an association with a common variant within 1p21.3. After replication in an independent cohort, we linked this genetic variant—associated with reduced SNX7 expression—to positive psychotic symptoms and executive function deficits in bipolar disorder. A series of post-mortem brain tissue and in vitro experiments suggested SNX7 downregulation to result in a caspase-8-driven activation of interleukin-1β and a subsequent induction of the brain kynurenine pathway. The current study demonstrates the potential of using biomarkers in genetic studies of psychiatric disorders, and may help to identify novel drug targets in bipolar disorder.

Summary.: Inhibitors of kynurenine 3-hydroxylase have previously been used to increase endogenous levels of kynurenic acid, an excitatory amino acid receptor antagonist. In the present electrophysiological study PNU 156561A was utilized to elevate endogenous concentrations of kynurenic acid and subsequent effects on the firing pattern of dopamine (DA) neurons of rat substantia nigra (SN) were analyzed. Pretreatment with PNU 156561A (40 mg/kg, i.v., 5–7 h) caused a five-fold increase in endogenous kynurenic acid levels in whole brain five to seven hours after administration and also evoked a significant increase in firing rate and bursting activity of nigral DA neurons. The results of the present study show that a moderate increase in endogenous kynurenic acid levels produces significant actions on the tonic glutamatergic control of the firing pattern of nigral DA neurons, and implicate kynurenine 3-hydroxylase inhibitors as novel antiparkinsonian agents.

Summary.: Previous studies have shown that systemic as well as local administration of the GABAB-receptor agonist baclofen is associated with a decrease in firing rate, a regularisation of firing rhythm and a decrease in burst firing activity of dopamine (DA) containing midbrain neurons. In the present electrophysiological study we have utilised the novel, selective and potent GABAB-receptor antagonist SCH 50911 in order to further analyse the importance of GABAB-receptors for the overall activity of rat nigral DA neurons. SCH 50911 given intravenously (1–64 mg/kg) or locally, by microiontophoretic techniques, was found to increase firing rate and to increase the burst firing activity of DA neurons. The present data suggest that the GABAB-receptor antagonist blocks somatodendritic receptors on nigral DA neurons. This GABA-receptor input appears to be of a tonic nature. It is proposed that the activation of nigral DA neurons may underlie the beneficial effects of GABAB-receptor antagonists in the modulation of cognition and that GABAB-receptor antagonists may be of therapeutic value in the treatment of Parkinson's disease.

Abstract:  Previous studies have shown that administration of γ-hydroxybutyric acid (GHBA) or the GABAB receptor agonist baclofen are associated with a decrease in firing rate, a regularisation of firing pattern and a decrease in burst activity of midbrain dopamine (DA) neurons in the substantia nigra (SN). In the present study we compared the ability of the novel GABAB receptor antagonist SCH 50911 and the selective antagonist of GHBA binding sites, NCS-382, to antagonise the effects of baclofen or GHBA, respectively, on the neuronal activity of DA neurons in anaesthetised rats. SCH 50911 (75 mg/kg, i.v.) was found to antagonise the decrease in firing rate, the regularisation of firing rhythm and the decrease of burst activity in DA cells, induced by baclofen (1–32 mg/kg, i.v.) or GHBA (12.5–1600 mg/kg, i.v.). NCS-382 (100 mg/kg, i.v.) did not affect the baclofen-induced changes in neuronal activity. Neither was the drug able to influence the GHBA-induced alterations in firing rate or in burst activity, although NCS-382 to some extent antagonised the regularisation of the firing pattern observed following low doses of GHBA (≤100 mg/kg). The results of the present study give further support for the notion that the GHBA-induced changes in neuronal activity of nigral dopamine neurons are mediated by stimulation of GABAB receptors.

Presents a letter to the editor about contemporary jazz music.

Most knowledge about the synthesis of human tumor necrosis factor (TNF)-α and its regulation derives from in vitro studies. The hypothesis that the syndrome of malaise, myalgia, and low fever observed after a vaccination with live attenuated yellow fever virus could be associated with increased synthesis of TNF was investigated. Plasma samples of 15 healthy subjects taken before and until day 2 (until day 11 in 5 of these subjects) after yellow fever vaccination, showed a significant increase of plasma TNF concentration on day 2 after vaccination and a second peak on day 7. Interleukin-1 receptor antagonist (IL-1ra) concentration was significantly elevated in all subjects on day 2 after vaccination. In a control group receiving non-live vaccinations, TNF and IL-1ra concentrations were unchanged. Thus, yellow fever vaccination represents a routine medical intervention that results in a reproducible increase in the plasma concentration of TNF and secondary cytokines. This may serve as a unique model for the study of the regulation of TNF synthesis in vivo.

The cellular response to heat shock requires massive adaptation of gene expression driven by the transcription factor HSF1, which assembles in nuclear stress bodies together with human satellite III RNA and numerous splicing factors. In this issue of The EMBO Journal, Ninomiya et al demonstrate that nuclear stress bodies serve as a platform for phosphorylation of the SR protein SRSF9 by the CLK1 kinase, which promotes retention of a large number of introns during the recovery phase from heat shock., (© 2020 The Authors.)