Proteomic and metabolomic profiling reveals time-dependent changes in hippocampal metabolism upon paroxetine treatment and biomarker candidates

Most of the commonly used antidepressants block monoamine reuptake transporters to enhance serotonergic or noradrenergic neurotransmission. Effects besides or downstream of monoamine reuptake inhibition are poorly understood and yet presumably important for the drugs' mode of action. In the present study we aimed at identifying hippocampal cellular pathway alterations in DBA/2 mice using paroxetine as a representative Selective Serotonin Reuptake Inhibitor (SSRI). Furthermore we identified biomarker candidates for the assessment of antidepressant treatment effects in plasma. Hippocampal protein levels were compared between chronic paroxetine- and vehicle-treated animals using in vivo¹⁵N metabolic labeling combined with mass spectrometry. We also studied the time course of metabolite level changes in hippocampus and plasma using a targeted polar metabolomics profiling platform. In silico pathway analyses revealed profound alterations related to hippocampal energy metabolism. Glycolytic metabolite levels acutely increased while Krebs cycle metabolite levels decreased upon chronic treatment. Changes in energy metabolism were influenced by altered glycogen metabolism rather than by altered glycolytic or Krebs cycle enzyme levels. Increased energy levels were reflected by an increased ATP/ADP ratio and by increased ratios of high-to-low energy purines and pyrimidines. In the course of our analyses we also identified myo-inositol as a biomarker candidate for the assessment of antidepressant treatment effects in the periphery. This study defines the cellular response to paroxetine treatment at the proteome and metabolome levels in the hippocampus of DBA/2 mice and suggests novel SSRI modes of action that warrant consideration in antidepressant development efforts.     

Layer-specific diffusion weighted imaging in human primary visual cortex in vitro

One of the most prominent characteristics of the human neocortex is its laminated structure. The first person to observe this was Francesco Gennari in the second half the 18th century: in the middle of the depth of primary visual cortex, myelinated fibres are so abundant that he could observe them with bare eyes as a white line. Because of its saliency, the stria of Gennari has a rich history in cyto- and myeloarchitectural research as well as in magnetic resonance (MR) microscopy. In the present paper we show for the first time the layered structure of the human neocortex with ex vivo diffusion weighted imaging (DWI). To achieve the necessary spatial and angular resolution, primary visual cortex samples were scanned on an 11.7 T small-animal MR system to characterize the diffusion properties of the cortical laminae and the stria of Gennari in particular. The results demonstrated that fractional anisotropy varied over cortical depth, showing reduced anisotropy in the stria of Gennari, the inner band of Baillarger and the deepest layer of the cortex. Orientation density functions showed multiple components in the stria of Gennari and deeper layers of the cortex. Potential applications of layer-specific diffusion imaging include characterization of clinical abnormalities, cortical mapping and (intra)cortical tractography. We conclude that future high-resolution in vivo cortical DWI investigations should take into account the layer-specificity of the diffusion properties.     

Rotator Cuff Tear Susceptibility Is Associated With Variants in Genes Involved in Tendon Extracellular Matrix Homeostasis

Rotator cuff tears (RCT) is a multifactorial disease with genetic factors contributing for the disease etiology. We hypothesized that genetic variants in genes involved in extracellular matrix (ECM) homeostasis may alter susceptibility to RCT. We evaluated 20 polymorphisms of genes involved in ECM homeostasis in 211 cases of full-thickness tears of the supraspinatus (N_females = 130; N_males = 81) and 567 age-matched controls (N_females = 317; N_males = 250). Multivariate logistic regressions were carried out with age, gender, genetic ancestry (based on the analysis of 61 biallelic short insertion/deletion polymorphisms), and common co-morbidities (diabetes, dyslipidemia, and smoking habits) as covariates. We observed that carriers of the rare allele of both studied variants of TGFB1, as well as their G/A (rs1800470/rs1800469) haplotype, were less susceptible to RCT (p < 0.05). In contrast, carriers of the G allele of MMP9 rs17576 (p = 0.014) or G/G haplotype (rs17576/rs17577; p < 0.001) had an increased risk for tendon tears. The presence of the T allele of MMP2 rs2285053 (p = 0.033), the T allele of MMP3 rs679620 (p = 0.024), and the TT-genotype of TIMP2 rs2277698 (p = 0.01) was associated with susceptibility to tears, especially in females. In males, the A allele of COL5A1 rs3196378 (p = 0.032) and the G allele of TGFBR1 rs1590 (p = 0.039) were independent risk factors for RCT. The C/T COL5A1 (rs3196378/rs11103544) haplotype was associated with a reduced risk of tears in males (p = 0.03). In conclusion, we identified the genetic variants associated with RCT susceptibility, thereby reinforcing the role of genes involved in the structure and homeostasis of the ECM of tendons in disease development. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 38:192–201, 2020     

Age effects on basic symptoms in the community: A route to gain new insight into the neurodevelopment of psychosis?

European Archives of Psychiatry and Clinical Neuroscience - Reports of limited clinical significance of attenuated psychotic symptoms before age 15/16 indicate an important role of neurodevelopment...     

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