Orbitofrontal cortex gray matter volumes in bipolar disorder patients: a region‐of‐interest MRI study

Objectives: Functional and postmortem studies suggest that the orbitofrontal cortex (OFC) is involved in the pathophysiology of bipolar disorder (BD). This anatomical magnetic resonance imaging (MRI) study examined whether BD patients have smaller OFC gray matter volumes compared to healthy comparison subjects (HC). Methods: Twenty‐eight BD patients were compared to 28 age‐ and gender‐matched HC. Subjects underwent a 1.5T MRI with 3D spoiled gradient recalled acquisition. Total OFC and medial and lateral subdivisions were manually traced by a blinded examiner. Images were segmented and gray matter volumes were calculated using an automated method. Results: Analysis of covariance, with intracranial volume as covariate, showed that BD patients and HC did not differ in gray matter volumes of total OFC or its subdivisions. However, total OFC gray matter volume was significantly smaller in depressed patients (n = 10) compared to euthymic patients (n = 18). Moreover, total OFC gray matter volumes were inversely correlated with depressive symptom intensity, as assessed by the Hamilton Depression Rating Scale. OFC gray matter volumes were not related to lithium treatment, age at disease onset, number of episodes, or family history of mood disorders. Conclusions: Our results suggest that abnormal OFC gray matter volumes are not a pervasive characteristic of BD, but may be associated with specific clinical features of the disorder.     

Cell‐ and region‐specific expression of depression‐related protein p11 (S100a10) in the brain

P11 (S100a10), a member of the S100 family of proteins, has widespread distribution in the vertebrate body, including in the brain, where it has a key role in membrane trafficking, vesicle secretion, and endocytosis. Recently, our laboratory has shown that a constitutive knockout of p11 (p11‐KO) in mice results in a depressive‐like phenotype. Furthermore, p11 has been implicated in major depressive disorder (MDD) and in the actions of antidepressants. Since depression affects multiple brain regions, and the role of p11 has only been determined in a few of these areas, a detailed analysis of p11 expression in the brain is warranted. Here we demonstrate that, although widespread in the brain, p11 expression is restricted to distinct regions, and specific neuronal and nonneuronal cell types. Furthermore, we provide comprehensive mapping of p11 expression using in situ hybridization, immunocytochemistry, and whole‐tissue volume imaging. Overall, expression spans multiple brain regions, structures, and cell types, suggesting a complex role of p11 in depression. J. Comp. Neurol. 525:955–975, 2017. © 2016 Wiley Periodicals, Inc.     

Akt‐dependent and Akt‐independent pathways are involved in protein synthesis activation during reloading of disused soleus muscle

Introduction: The purpose of our study was to assess the contribution of insulin growth factor‐1–dependent and phosphatidic acid‐dependent signaling pathways to activation of protein synthesis (PS) in rat soleus muscle during early recovery from unloading. Methods: Wistar rats were divided into: Control, 14HS [14‐day hindlimb suspension (HS)], 3R+placebo (3‐day reloading + saline administration), 3R+Wort (3‐day reloading + wortmannin administration), 3R+But (3‐day reloading + 1‐butanol administration). SUnSET and Western blot analyses were used in this study. Results: Wortmannin and 1‐butanol induced a decrease in protein kinase B (phospho‐Akt) and the rate of PS (P < 0.05) versus Control. In 3R+placebo and 3R+Wort, phosphorylation of glycogen synthase kinase 3 beta (phospho‐GSK‐3β) was increased versus Control (P < 0.05). Wortmannin administration during reloading did not alter phospho‐p70S6K (70 kDa ribosomal protein S6 kinase) versus 3R+placebo. In 3R+But, there was a decline in phospho‐GSK‐3β versus 3R+placebo and Control. In 3R+But, there was a decrease in phopho‐p70S6K (P < 0.05) versus 3R+placebo. Conclusions: These results suggest that PS activation during 3‐day reloading following 14HS involves both Akt‐dependent and Akt‐independent pathways. Muscle Nerve 55 : 393–399, 2017     

Characterization of the mitofusin 2 R94W mutation in a knock‐in mouse model

Charcot‐Marie‐Tooth disease (CMT) comprises a group of heterogeneous peripheral axonopathies affecting 1 in 2,500 individuals. As mutations in several genes cause axonal degeneration in CMT type 2, mutations in mitofusin 2 (MFN2) account for approximately 90% of the most severe cases, making it the most common cause of inherited peripheral axonal degeneration. MFN2 is an integral mitochondrial outer membrane protein that plays a major role in mitochondrial fusion and motility; yet the mechanism by which dominant mutations in this protein lead to neurodegeneration is still not fully understood. Furthermore, future pre‐clinical drug trials will be in need of validated rodent models. We have generated a Mfn2 knock‐in mouse model expressing Mfn2^R94W, which was originally identified in CMT patients. We have performed behavioral, morphological, and biochemical studies to investigate the consequences of this mutation. Homozygous inheritance leads to premature death at P1, as well as mitochondrial dysfunction, including increased mitochondrial fragmentation in mouse embryonic fibroblasts and decreased ATP levels in newborn brains. Mfn2^R94W heterozygous mice show histopathology and age‐dependent open‐field test abnormalities, which support a mild peripheral neuropathy. Although behavior does not mimic the severity of the human disease phenotype, this mouse can provide useful tissues for studying molecular pathways associated with MFN2 point mutations.     

Coordinate‐based (ALE) meta‐analysis of brain activation in patients with fibromyalgia

There are an increasing number of neuroimaging studies that allow a better understanding of symptoms, neural correlates and associated conditions of fibromyalgia. However, the results of these studies are difficult to compare, as they include a heterogeneous group of patients, use different stimulation paradigms, tasks, and the statistical evaluation of neuroimaging data shows high variability. Therefore, this meta‐analytic approach aimed at evaluating potential alterations in neuronal brain activity or structure related to pain processing in fibromyalgia syndrome (FMS) patients, using quantitative coordinate‐based “activation likelihood estimation” (ALE) meta‐analysis. 37 FMS papers met the inclusion criteria for an ALE analysis (1,264 subjects, 274 activation foci). A pooled ALE analysis of different modalities of neuroimaging and additional analyses according functional and structural changes indicated differences between FMS patients and controls in the insula, amygdala, anterior/mid cingulate cortex, superior temporal gyrus, the primary and secondary somatosensory cortex, and lingual gyrus. Our analysis showed consistent results across FMS studies with potential abnormalities especially in pain‐related brain areas. Given that similar alterations have already been demonstrated in patients with other chronic pain conditions and the lack of adequate control groups of chronic pain subjects in most FMS studies, it is not clear however, whether these findings are associated with chronic pain in general or are unique features of patients with FMS. Hum Brain Mapp 37:1749–1758, 2016. © 2016 Wiley Periodicals, Inc .     

Perisynaptic Schwann cells phagocytose nerve terminal debris in a mouse model of Guillain‐Barré syndrome

In mouse models of acute motor axonal neuropathy, anti‐ganglioside antibodies (AGAbs) bind to motor axons, notably the distal nerve, and activate the complement cascade. While complement activation is well studied in this model, the role of inflammatory cells is unknown. Herein we aimed to investigate the contribution of phagocytic cells including macrophages, neutrophils and perisynaptic Schwann cells (pSCs) to distal nerve pathology. To observe this, we first created a subacute injury model of sufficient duration to allow inflammatory cell recruitment. Mice were injected intraperitoneally with an anti‐GD1b monoclonal antibody that binds strongly to mouse motor nerve axons. Subsequently, mice received normal human serum as a source of complement. Dosing was titrated to allow humane survival of mice over a period of 3 days, yet still induce the characteristic neurological impairment. Behaviour and pathology were assessed in vivo using whole‐body plethysmography and post‐sacrifice by immunofluorescence and flow cytometry. ex vivo nerve‐muscle preparations were used to investigate the acute phagocytic role of pSCs following distal nerve injury. Following complement activation at distal intramuscular nerve sites in the diaphragm macrophage localisation or numbers are not altered, nor do they shift to a pro‐ or anti‐inflammatory phenotype. Similarly, neutrophils are not significantly recruited. Instead, ex vivo nerve‐muscle preparations exposed to AGAb plus complement reveal that pSCs rapidly become phagocytic and engulf axonal debris. These data suggest that pSCs, rather than inflammatory cells, are the major cellular vehicle for axonal debris clearance following distal nerve injury, in contrast to larger nerve bundles where macrophage‐mediated clearance predominates.     

Bcl‐2 expression in a papillary tumor of the pineal region

Neuroepithelial papillary tumor of the pineal region (PTPR) has been described by several groups and recognized by the 2007 World Health Organization Classification of Tumors of the Central Nervous System. The proto‐oncogen Blc‐2 can function as an apoptosis suppressor and can promote neoplastic transformation. It may also be involved in neuroendocrine differentiation in some tumors. As PTPRs express neuroendocrine markers, we investigated the expression of Bcl‐2 in tumoral cells of a new case of PTPR in a 42‐year‐old woman. Bcl‐2 immunostaining was detected in the cytoplasm of the tumoral cells; staining intensity was heterogeneous from cell to cell and more intense in papillary areas. This intense expression of Bcl‐2 in one case of PTPR with a high proliferation index (8%) might be related to the malignancy of this neoplasm. It will be interesting to investigate the prognosis impact of Bcl‐2 expression in a large series of PTPRs.     

Loss of NECL1, a novel tumor suppressor,can be restored in glioma by HDAC inhibitor‐Trichostatin A through Sp1 binding site

Nectin‐like molecule 1 (NECL1)/CADM3/IGSF4B/TSLL1/SynCAM3 is a neural tissue‐specific immunoglobulin‐like cell–cell adhesion molecule downregulated at the mRNA level in 12 human glioma cell lines. Here we found that the expression of NECL1 was lost in six glioma cell lines and 15 primary glioma tissues at both RNA and protein levels. Re‐expression of NECL1 into glioma cell line U251 would repress cell proliferation in vitro by inducing cell cycle arrest. And also NECL1 could decrease the growth rate of tumors in nude mice in vivo. To further investigate the mechanism why NECL1 was silenced in glioma, the basic promoter region located at ?271 to +81 in NECL1 genomic sequence was determined. DNA bisulfite sequencing was performed to study the methylation status of CpG islands in NECL1 promoter; however, no hypermethylated CpG site was found. Additionally, the activity of histone deacetylase (HDACs) in glioma was higher than that in normal brain tissues, and the expression of NECL1 in glioma cell lines could be reactivated by HDACs inhibitor‐Trichostatin A (TSA). So the loss of NECL1 in glioma was at least partly caused by histone deacetylation. Luciferase reporter assays, chromatin immunoprecipitation and co‐immunoprecipitation (co‐IP) assays indicated that Sp1 played an important role in this process by binding to either HDAC1 in untreated glioma cells or p300/CBP in TSA treated cells. Our finding suggests that NECL1 may act as a tumor suppressor in glioma and loss of it in glioma may be caused by histone deacetylation. © 2008 Wiley‐Liss, Inc.     

Neonatal exposure to MK‐801 reduces mRNA expression of mGlu3 receptors in the medial prefrontal cortex of adolescent rats

Schizophrenia is considered as a “neurodegenerative” and “neurodevelopmental” disorder, the pathophysiology of which may include hypofunction of the N‐methyl‐d ‐aspartate receptor (NMDA‐R) or subsequent pathways. Accordingly, administration of NMDA‐R antagonists to rodents during the perinatal period may emulate some core pathophysiological aspects of schizophrenia. The effect of 4‐day (postnatal day; PD 7–10) administration of MK‐801, a selective NMDA‐R antagonist, on gene expression in the medial prefrontal cortex (mPFC), hippocampus, and amygdala was evaluated using quantitative polymerase chain reaction methods. Specifically, we sought to determine whether genes related to Glu transmissions, for example those encoding for NMDA‐Rs, metabotropic Glu receptors (mGluRs), or Glu transporters, were altered by neonatal treatment with MK‐801. Model rats showed downregulation of the mGluR3 subtype in the mPFC around puberty, especially at PD 35 in response to MK‐801 or during ontogenesis without pharmacological manipulations. Genes encoding for other mGluRs subtypes, that is NMDA‐Rs and Glu transporters, were not affected by the neonatal insult. These results suggest that NMDA‐R antagonism in the early course of development modulates the expression of mGluR3 in mPFC around puberty. Thus, mGluR3 may serve as a potential target to prevent the onset and progression of schizophrenia. Synapse 68:202–208, 2014 . © 2014 Wiley Periodicals, Inc.     

Tenascin C and tenascin R similarly prevent the formation of myelin membranes in a RhoA‐dependent manner,but antagonistically regulate the expression of myelin basic protein via a separate pathway

Membrane formation and the initiation of myelin gene expression are hallmarks of the differentiation of oligodendrocytes from their precursors. Here, we compared the roles of the two related extracellular matrix (ECM) glycoproteins Tenascin C (Tnc) and Tenascin R (Tnr) in oligodendrocyte differentiation. Oligodendrocyte precursors from Tnr‐deficient mice exhibited reduced differentiation, as revealed by retarded expression of myelin basic protein (MBP) in culture. This could be rescued with purified Tnr. In contrast, when we cultured oligodendrocytes on a Tnc‐containing, astrocyte‐derived ECM, they barely expressed MBP. This inhibition could be overcome when we used ECM from astrocytes deficient for Tnc, suggesting that Tnc inhibits differentiation. In contrast to their antagonistic effect on differentiation, both Tnc and Tnr similarly inhibited morphologic maturation. When oligodendrocytes were cultured on the purified glycoproteins, process elaboration and membrane expansion were reduced. Both Tnc and Tnr interfered with the activation of the small GTPase RhoA. Conversely, RhoA and Rac1 activation induced by cytotoxic necrotizing factor 1 (CNF1) increased the formation of myelin membranes, whereas Y27632‐mediated inhibition of the Rho‐cascade prevented it without, however, affecting the fraction of MBP‐expressing cells. Because Tnc and Tnr play antagonistic roles for differentiation and comparably inhibit morphologic maturation, we conclude that independent molecular pathways regulate these processes. © 2009 Wiley‐Liss, Inc.     

Clinical and genetic associations of autoantibodies to 3‐hydroxy‐3‐methyl‐glutaryl‐coenzyme a reductase in patients with immune‐mediated myositis and necrotizing myopathy

Introduction: Inhibition of 3‐hydroxy‐3‐methyl‐glutaryl‐coenzyme A reductase (HMGCR) with statins may trigger idiopathic inflammatory myositis (IIM) or immune‐mediated necrotizing myopathy (IMNM). Anti‐HMGCR antibodies have been detected in patients with IIM/IMNM. We aimed to determine the associations of anti‐HMGCR in IIM/IMNM. Methods: Anti‐HMGCR antibodies were detected by ELISA in sera from patients with IIM/IMNM. Results: Anti‐HMGCR antibodies were detected in 19 of 207 patients with IIM/IMNM, and there was a trend toward an association with male gender (P = 0.079). Anti‐HMGCR antibodies were associated strongly with statin exposure (OR = 39, P = 0.0001) and HLA‐DRB1*11 (OR = 50, P < 0.0001). The highest risk for development of anti‐HMGCR antibodies was among HLA‐DR11 carriers exposed to statins. Univariate analysis showed a strong association of anti‐HMGCR antibodies with diabetes mellitus (P = 0.008), which was not confirmed by multiple regression. Among anti‐HMGCR⁺ patients there was a trend toward increased malignancy (P = 0.15). Conclusions: Anti‐HMGCR antibodies are seen in all subtypes of IIM and IMNM and are associated strongly with statin use and HLA‐DR11. Muscle Nerve 52 : 196–203, 2015