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Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is a master regulator of cellular protective processes. Rheumatic diseases are chronic conditions characterized by inflammation, pain, tissue damage and limitations in function. Main examples are rheumatoid arthritis, systemic lupus erythematosus, osteoarthritis and osteoporosis. Their high prevalence constitutes a major health problem with an important social and economic impact. A wide range of evidence indicates that Nrf2 may control different mechanisms involved in the physiopathology of rheumatic conditions. Therefore, the appropriate expression and balance of Nrf2 is necessary for regulation of oxidative stress, inflammation, immune responses, and cartilage and bone metabolism. Numerous studies have demonstrated that Nrf2 deficiency aggravates the disease in experimental models while Nrf2 activation results in immunoregulatory and anti-inflammatory effects. These reports reinforce the increasing interest in the pharmacologic regulation of Nrf2 and its potential applications. Nevertheless, a majority of Nrf2 inducers are electrophilic molecules which may present off-target effects. In recent years, novel strategies have been sought to modulate the Nrf2 pathway which has emerged as a therapeutic target in rheumatic conditions. [ABSTRACT FROM AUTHOR]

Abstract: The mammalian central nervous system, due to its interaction with the environment, must be endowed with plasticity. Conversely, the nervous tissue must be substantially static to ensure connectional invariability. Structural plasticity can be viewed as a compromise between these requirements. In adult mammals, brain structural plasticity is strongly reduced with respect to other animal groups in the phylogenetic tree. It persists under different forms, which mainly consist of remodeling of neuronal shape and connectivity, and, to a lesser extent, the production of new neurons. Adult neurogenesis is mainly restricted within two neurogenic niches, yet some gliogenic and neurogenic processes also occur in the so-called non-neurogenic tissue, starting from parenchymal progenitors. In this review we focus on a population of immature, non-newly generated neurons in layer II of the cerebral cortex, which were previously thought to be newly generated since they heavily express the polysialylated form of the neural cell adhesion molecule and doublecortin. These unusual neurons exhibit characteristics defining an additional type of structural plasticity, different from either synaptic plasticity or adult neurogenesis. Evidences concerning their morphology, antigenic features, ultrastructure, phenotype, origin, fate, and reaction to different kind of stimulations are gathered and analyzed. Their possible role is discussed in the context of an enriched complexity and heterogeneity of mammalian brain structural plasticity. [Copyright &y& Elsevier]

In adult cornu ammonis hippocampi, erythropoietin (EPO) expression drives the differentiation of new neurons, independent of DNA synthesis, and increases dendritic spine density. This substantial brain hardware upgrade is part of a regulatory circle: during motor-cognitive challenge, neurons experience "functional" hypoxia, triggering neuronal EPO production, which in turn promotes improved performance. Here, we show an unexpected involvement of resident microglia. During EPO upregulation and stimulated neurodifferentiation, either by functional or inspiratory hypoxia, microglia numbers decrease. Treating mice with recombinant human (rh)EPO or exposure to hypoxia recapitulates these changes and reveals the involvement of neuronally expressed IL-34 and microglial CSF1R. Surprisingly, EPO affects microglia in phases, initially by inducing apoptosis, later by reducing proliferation, and overall dampens microglia activity and metabolism, as verified by selective genetic targeting of either the microglial or pyramidal neuronal EPO receptor. We suggest that during accelerating neuronal differentiation, EPO acts as regulator of the CSF1R-dependent microglia. [Display omitted] • Microglia transiently respond to EPO by apoptosis, followed by abridged proliferation • Reduction of microglia allows undisturbed fast differentiation of immature neurons • Microglial and pyramidal EPOR are critical for neurodifferentiation in CA1 on EPO • EPO acts as regulator of neuronally expressed IL-34 and CSF1R-dependent microglia Fernandez Garcia-Agudo et al. report prominent EPO effects on neurodifferentiation that depend on a counterbalance between microglia and neurons. Microglia respond to EPO by transient apoptosis followed by dampened activity and reduced proliferation, allowing undisturbed differentiation of immature neuronal subpopulations. This ultimately results in increased numbers of mature hippocampal neurons. [ABSTRACT FROM AUTHOR]

The expression of the polysialylated neural cell adhesion molecule (PSA-NCAM) is increased in the hippocampus after chronic restraint stress (CRS) and may play a permissive role in structural changes that include dendrite reorganization in dentate gyrus (DG) and CA3 pyramidal neurons and suppression of neurogenesis in DG. We report that chronic oral corticosterone (CORT) administration decreases the number of PSA-NCAM immunoreactive granule neurons in the adult rat dentate gyrus, and the available evidence suggests that this is an indirect effect of CORT, possibly involving excitatory amino acids, that may not be directly related to neurogenesis. Because CORT treatment reduces but does not eliminate PSA-NCAM expression, the present results do not exclude a permissive role for PSA-NCAM in CORT or CRS-induced structural plasticity in hippocampus. [Copyright &y& Elsevier]

The production of new neurons declines during adulthood and persists, although at very low levels, in the aged hippocampus. Since neurogenesis in young adults has been related to learning and memory, its reduction may contribute to the age-related impairments in these abilities. Adrenalectomy (ADX) enhances neurogenesis in the aged hippocampus, although it also induces neuronal cell death. Since the administration of an NMDA receptor antagonist enhances neurogenesis in young adult rats without deleterious morphological effects, we have tested whether neurogenesis could be reactivated in aged rats. Our study shows that cell proliferation, cell death, neurogenesis and the number of radial glia-like nestin immunoreactive cells decrease in middle-age (10 months) and remain very low in the aged hippocampus. Injection of the NMDA receptor antagonist to aged rats increases significantly the number of proliferating cells, new neurons and radial glia-like cells in the hippocampus. [Copyright &y& Elsevier]

The control of neuritogenesis is crucial for the development, maturation and regeneration of the nervous system. The collapsin response-mediated protein 4 (CRMP-4) is a member of a family of proteins that are involved in neuronal differentiation and axonal outgrowth. In rodents, this protein is expressed in recently generated neurons such as some granule neurons of the dentate gyrus, as well as in certain differentiated neurons undergoing neurite outgrowth or synaptogenesis during adulthood. Since CRMP-4 protein appears to be highly conserved throughout the evolutionary scale, we have used immunocytochemistry to study its distribution in the lizard cerebral cortex. We have found pronounced CRMP-4 immunolabeling in certain neurons of the medial cortex, the homologous region to the dentate gyrus, but also in the dorsal and lateral cortices. Double labeling with 5′-BrdU indicated that these medial cortex neurons were recently generated. However, it is also possible that many of these cells were not new but undergoing some kind of plasticity implicating neurite outgrowth. Similar CRMP-4-labeled neurons and processes were observed in subcortical regions as the PDVR and the nucleus sphericus. Our results show for the first time the expression of CRMP-4 in a reptile brain, where it appears to be expressed in regions where adult neurogenesis and/or neurite outgrowth occur. [Copyright &y& Elsevier]

The polysialylated form of the neural cell adhesion molecule (PSA-NCAM) continues to be expressed in the adult hippocampus, mainly in a subset of neurons located in the innermost portion of the granule cell layer. PSA-NCAM immunoreactive neurons have also been described outside this layer in humans, where they are severely reduced in schizophrenic brains. Given this important clinical implication, we were interested in finding whether similar neurons existed in the adult rat hippocampus and to characterize their distribution, morphology and phenotype. PSA-NCAM immunocytochemistry reveals labeled neurons in the subiculum, fimbria, alveus, hilus, and stratum oriens, lucidum and radiatum of CA3 and CA1. They are mainly distributed in the ventral hippocampus, and have polygonal or fusiform somata with multipolar or bipolar morphology. These neurons show long straight dendrites, which reach several strata and even enter the fimbria and the alveus. These dendrites are often varicose, appear devoid of excrescences and apparently do not show spines. Most of these neurons display GABA immunoreactivity and further analysis has shown that a subpopulation expresses calretinin, but not somatostatin, neuropeptide Y, parvalbumin, calbindin or NADPH diaphorase. Our study demonstrates that there is an important subpopulation of PSA-NCAM immunoreactive neurons, many of which can be considered interneurons, outside the rat granule cell layer, probably homologous to those described in the human hippocampus. The presence of the polysialylated form of NCAM in these neurons could indicate that they are undergoing continuous remodeling during adulthood and may have an important role in hippocampal structural plasticity. [Copyright &y& Elsevier]

Administration of NMDA receptor antagonists upregulates the expression of the polysialylated form of the neural cell adhesion molecule (PSA-NCAM) in the adult hippocampus. Since the piriform cortex is also populated by PSA-NCAM immunoreactive neurons during adulthood, we sought to characterize them in detail and to test whether NMDA receptor antagonists also modulate PSA-NCAM in this cortical region. PSA-NCAM immunoreactivity is located mainly in layer II, where many neurogliaform and some pyramidal–semilunar transitional neurons are labeled. Many large neurons in layer III and endopiriform nucleus also express PSA-NCAM. Interestingly, some small labeled cells resembling migratory neuroblasts appear in these layers and in the ventral end of the corpus callosum subjacent to the piriform cortex. These putative migratory cells and some neurogliaform neurons in layer II do not express NeuN, a marker of differentiated neurons. Many of these PSA-NCAM immunoreactive cells also express doublecortin, a molecule involved in neuronal migration. The number of PSA-NCAM immunoreactive neurogliaform neurons increases significantly 7 days after the administration of an NMDA receptor antagonist. Moreover, 21 days after the treatment we observe a significant increase in the number of doublecortin expressing cells in the deep layers of the piriform cortex. These results expand the current knowledge of the neuronal populations expressing PSA-NCAM in the piriform cortex, suggesting that some of these cells could be involved in structural plastic events such as axonal outgrowth, synaptogenesis or even neuronal migration. Similar to the hippocampus, NMDA receptors appear to play a critical role in these processes in the adult piriform cortex. [Copyright &y& Elsevier]

Abstract: We investigated the association between ST8SIAII and schizophrenia in a sample of Spanish origin. We found that the G allele (P=0.044) and the AG genotype (P=0.040) of rs3759916 were associated in females. The ACAG haplotype (rs3759914, rs3759915, rs3759916 and rs2305561) was associated in males (P=0.028). [Copyright &y& Elsevier]

Different lines of evidence indicate that the structure and physiology of the basal ganglia and the thalamus is disturbed in schizophrenia. However, it is unknown whether the volume and shape of these subcortical structures are affected in schizophrenia with auditory hallucinations (AH), a core positive symptom of the disorder. We took structural MRI from 63 patients with schizophrenia, including 36 patients with AH and 27 patients who had never experienced AH (NAH), and 51 matched healthy controls. We extracted volumes for the left and right thalamus, globus pallidus, putamen, caudate and nucleus accumbens. Shape analysis was also carried out. When comparing to controls, the volume of the right globus pallidus, thalamus, and putamen, was only affected in AH patients. The volume of the left putamen was also increased in individuals with AH, whereas the left globus pallidus was affected in both groups of patients. The shapes of right and left putamen and thalamus were also affected in both groups. The shape of the left globus pallidus was only altered in patients lacking AH, both in comparison to controls and to cases with AH. Lastly, the general PANSS subscale was correlated with the volume of the right thalamus, and the right and left putamen, in patients with AH. We have found volume and shape alterations of many basal ganglia and thalamus in patients with and without AH, suggesting in some cases a possible relationship between this positive symptom and these morphometric alterations. • The volume of several basal ganglia was only affected in AH patients. • The volume of the left globus pallidus was affected in both groups of patients. • The shapes of right and left putamen and thalamus were also affected in both groups. • The shape of the left globus pallidus was only altered in patients lacking AH. [ABSTRACT FROM AUTHOR]

Down syndrome (DS) is the most common genetic disorder associated with intellectual disability. To study this syndrome, several mouse models have been developed. Among the most common is the Ts65Dn model, which mimics most of the alterations observed in DS. Ts65Dn mice, as humans with DS, show defects in the structure, density, and distribution of dendritic spines in the cerebral cortex and hippocampus. Fasudil is a potent inhibitor of the RhoA kinase pathway, which is involved in the formation and stabilization of dendritic spines. Our study analysed the effect of early chronic fasudil treatment on the alterations observed in the hippocampus of the Ts65Dn model. We observed that treating Ts65Dn mice with fasudil induced an increase in neural plasticity in the hippocampus: there was an increment in the expression of PSA-NCAM and BDNF, in the dendritic branching and spine density of granule neurons, as well as in cell proliferation and neurogenesis in the subgranular zone. Finally, the treatment reduced the unbalance between excitation and inhibition present in this model. Overall, early chronic treatment with fasudil increases cell plasticity and eliminates differences with euploid animals. • Fasudil treatment recovers dendritic trees in granule neurons of Ts65Dn mice. • Fasudil treatment increases spine density in granule neurons of Ts65Dn mice. • Fasudil treatment increases structural plasticity in the hippocampus of Ts65Dn mice. • Fasudil treatment recovers cell proliferation rate in dentate gyrus of Ts65Dn mice. • Fasudil infusion reduces the excess of inhibitory puncta in the hippocampus of Ts65Dn. [ABSTRACT FROM AUTHOR]

Abstract: Several lines of evidence indicate that alterations in the structure of neural circuits and inhibitory neurotransmission underlie the physiopathogenesis of schizophrenia. Most of the studies on these parameters have been focused on cortical regions and, despite the crucial role of the amygdala in this psychiatric disorder, there is less information on this region. In order to expand this knowledge, we have studied the expression of molecules related to inhibitory neurotransmission and structural plasticity in rats subjected to post-weaning isolation rearing, an animal model that reproduces several core symptoms of schizophrenia. We have analyzed, using qRT-PCR and immunohistochemistry, the expression of synaptophysin, GAD65, GAD67, the neural cell adhesion molecule (NCAM), its polysialylated form (PSA-NCAM) and its synthesizing enzymes (St8siaII and St8SiaIV). Isolation-reared rats showed significant increases in the expression of GAD67 protein in the centromedial, medial and basolateral amygdaloid nuclei, but no significant changes in GAD65 or synaptophysin expression were found in these regions. The expression of PSA-NCAM and NCAM was significantly increased in the basolateral and medial nuclei respectively. Our results indicate that isolation-rearing influences positively inhibitory neurotransmission and neuronal structural plasticity in the amygdala, probably through PSA-NCAM. These findings are in contrast to reports describing decreased expression of molecules related to inhibitory neurotransmission in the amygdala of schizophrenic patients. Consequently, although the social isolation rearing model can reproduce some of the behavioral traits of schizophrenics it may fail to reproduce some of the neurobiological features of this disorder, particularly in the amygdala. [Copyright &y& Elsevier]

Although the precise mechanism of action of antidepressant drugs remains elusive, the neuroplastic hypothesis has gained acceptance during the last two decades. Several studies have shown that treatment with antidepressants such as Fluoxetine is associated with enhanced plasticity in control animals, especially in regions such as the visual cortex, the hippocampus and the medial prefrontal cortex. More recently, the basolateral amygdala has been shown to be affected by Fluoxetine leading to a reopening of critical period-like plasticity in the fear and aggression circuits. One of the key elements triggering this type of brain plasticity are inhibitory networks, especially parvalbumin interneurons. However, recent work on fast-acting antidepressants has shown also an important role for somatostatin interneurons. Here we show that Fluoxetine reorganizes inhibitory circuits through increased expression of the plasticity-related molecule PSA-NCAM which regulates interneuronal structure and connectivity. In addition, we demonstrate that treatment with this antidepressant alters the structure of somatostatin interneurons both at the level of dendritic spines and of axonal en passant boutons . Our findings suggest that new strategies targeting somatostatin interneuron activity might help us to better understand depression and the action of antidepressants. [ABSTRACT FROM AUTHOR]

The adult brain retains a substantial capacity for synaptic reorganization, which includes a wide range of modifications from molecular to structural plasticity. Previous reports have demonstrated that the structural remodeling of excitatory neurons seems to occur in parallel to changes in GABAergic neurotransmission. The function of neuronal inhibitory networks can be modified through GABAA receptors, which have a binding site for benzodiazepines (BZ). Although BZs are among the most prescribed drugs, is not known whether they modify the structure and connectivity of pyramidal neurons. In the present study we wish to elucidate the impact of a chronic treatment of 21 days with diazepam (2 mg/kg, ip), a BZ that acts as an agonist of GABAA receptors, on the structural plasticity of pyramidal neurons in the prefrontal cortex of adult mice. We have examined the density of dendritic spines and the density of axonal en passant boutons in the cingulate cortex. Although no significant changes were observed in their anxiety levels, animals treated with diazepam showed a decrease in the density of spines in the apical dendrites of pyramidal neurons. Most GFP-expressing en passant boutons in the upper layers of the cingulate cortex had an extracortical origin and no changes in their density were detected after diazepam treatment. These results indicate that the chronic potentiation of GABAergic synapses can induce the structural remodeling of postsynaptic elements in pyramidal neurons. [ABSTRACT FROM AUTHOR]

Diabetes mellitus patients are at increased risk of developing depression, although the neurobiological bases of this comorbidity are not yet fully understood. These patients show CNS alterations, similar to those found in major depression, including changes in the structure and neurotransmission of excitatory neurons. However, although depressive patients and animal models also display alterations in inhibitory networks, little is known about the effects of diabetes on interneurons. Our main objective was to study the impact of diabetes on interneurons of the medial prefrontal cortex (mPFC), one of the regions most affected by major depression. For this purpose we have induced diabetes with high-dose streptozotozin in transgenic mice displaying fluorescent interneurons. These animals showed a depressive-like behavior (increased immobility time in tail suspension test) in parallel with reductions in interneuronal dendritic arborization and in the expression of GAD67, the enzyme that synthetizes the inhibitory neurotransmitter GABA. However, the levels of PSA-NCAM, a plasticity-related molecule exclusively expressed by interneurons in the mPFC, were unaltered in the different regions and layers of this cortical area. Interestingly, diabetic mice also showed increased levels of synaptophysin, a synaptic vesicle protein. These results indicate that the structure and neurotransmission of interneurons is altered in the mPFC of diabetic mice and suggest that these changes may play a key role in the depressive symptoms associated to diabetes. [ABSTRACT FROM AUTHOR]

Zinc is an essential trace element that is critical for a large number of structural proteins, enzymatic processes and transcription factors. In the brain, zinc ions are involved in synaptic transmission. The homeostasis of zinc is crucial for cell survival and function, and cells have developed a wide variety of systems to control zinc concentration. Alterations in free zinc concentration have been related with brain dysfunction. Down Syndrome individuals present alterations in free zinc concentration and in some of the proteins related with zinc homeostasis. We have analyzed the amount of free zinc and the zinc chelating protein metallothionein 3 in the astrocytes using primary cultures of the murine model Ts65Dn. We have observed a higher number of zinc positive spots in the cytoplasm of trisomic astrocytes but a decrease in the total concentration of total intracellular free zinc concentration (including the spots) respect to control astrocytes. Using FM1-43 staining, we found that the endocytic function remains unaltered. Therefore, a possible explanation for this lower concentration of free zinc could be the higher concentration of metallothionein 3 present in the cytoplasm of trisomic astrocytes. The blockade of metallothionein 3 expression using an specific siRNA induced an increase in the concentration of free zinc in basal conditions but failed to increase the uptake of zinc after incubation with zinc ions. [ABSTRACT FROM AUTHOR]

The effects of intense stressors can last a long time and may lead to the development of psychiatric disorders, including posttraumatic stress disorder. The basolateral amygdala (BLA) plays a critical role in these diseases and is extremely sensitive to stress. Here, we explored in male and female mice the long-term (35 days) impact of a 24-h restraint stress on BLA circuitry. We used Thy1 -YFP mice to discriminate 2 subpopulations of excitatory neurons, which participate in "Fear-On" (Thy1-) and "Fear-Off" (Thy1+) circuits. The stress decreased the density of parvalbumin (PV) + inhibitory neurons in both sexes but did not alter their dendritic complexity. We also analyzed the perisomatic input of basket interneurons on Thy1 + and Thy1 - neurons, finding sex dependent effects. In males, we did not find alterations in the density of PV+ puncta or in that of cannabinoid receptor 1 (CB1R) + puncta from cholecystokinin+ basket cells. By contrast, in females we found increased the density of PV+ puncta on Thy1+ neurons and reduced on the Thy1- neurons. This adverse experience also reduced in the long term the density of CB1R+ puncta both on Thy1 + and Thy1- cells in females. The expression of the activity marker FosB was not altered in PV+ interneurons and in Thy1 + neurons of stressed animals. The density of perineuronal nets, a specialized region of the extracellular matrix, which covers particularly PV+ interneurons and regulates their connectivity, was increased by stress in male mice. Our findings indicate that a single stressful event can produce long-term alterations in the inhibitory circuits of the BLA, especially on PV+ neurons and their plasticity, and that there is a differential impact depending on the sex and the fear-related circuits involved. • A single intense stressful event alters in the long term the inhibitory circuits of the basolateral amygdala. • Alterations are prominent on PV+ neurons and molecules related to their plasticity. • Differential impact on the inhibitory input of excitatory neurons depending on the fear-related circuit they are involved in. • Some of the long term effects of stress observed in amygdaloid inhibitory circuits are sex specific. [ABSTRACT FROM AUTHOR]

Abstract: Neuroimaging has revealed structural abnormalities in the amygdala of different psychiatric disorders. The polysialylated neural cell adhesion molecule (PSA-NCAM), a molecule related to neuronal structural plasticity, which expression is altered in schizophrenia, major depression and in animal models of these disorders, may participate in these changes. However, PSA-NCAM has not been studied in the human amygdala. To know whether its expression and that of presynaptic markers, was affected in psychiatric disorders, we have analyzed post-mortem sections from the Stanley Neuropathology Consortium, which includes controls, schizophrenia, bipolar and major depression patients. PSA-NCAM was expressed in neuronal somata and neuropil puncta, many of which corresponded to interneurons. Depressed patients showed decreases in PSA-NCAM expression in the basolateral and basomedial amygdala; synaptophysin and GAD67 were also decreased, while VGLUT-1 was increased, in different nuclei. Increases in PSA-NCAM expression were found in the lateral nucleus of bipolar patients; synaptophysin and GAD67 were reduced, and VGLUT-1 increased, in their basolateral and lateral nuclei. The expression of synaptophysin and GAD67 was downregulated in the basolateral nucleus of schizophrenics. These results indicate that inhibitory and excitatory amygdaloid circuits are affected in these disorders and that abnormal PSA-NCAM expression in depressive and bipolar patients may underlie these alterations. [Copyright &y& Elsevier]

• MCP-1 is expressed by neurons in the rat neocortex. • Neurons expressing low levels of MCP-1 in the rat neocortex are excitatory. • Neurons expressing high levels of MCP-1- in the rat neocortex are inhibitory and co-express CCK/CBR1. • Neurons expressing high levels of MCP-1 in the rat neocortex are metabolically active. Chemokines are small, secreted molecules that mediate inflammatory reactions. Neurons and astrocytes constitutively express chemokines implicated in the process of neuroinflammation associated with neurodegenerative diseases. The monocyte chemoattractant protein-1 (MCP-1) has been widely related to this process. However, the constitutive expression of this molecule by neurons has not been elucidated so far. In this study, we set out to characterize the neurochemical phenotype of MCP-1-expressing neurons in the rat neocortex to infer its role in basal conditions. We observed the presence of two populations of neurons expressing MCP-1: One population of cells with weak expression of MCP-1 corresponding to principal neurons (Tbr-1 positive) and a second population with high expression of MCP-1 corresponding to inhibitory neurons (GAD-67 positive), in particular to CCK/CBR1 interneurons. Moreover, high MCP-1-expressing neurons were metabolically active (pCREB positive). The population of CCK interneurons that co-localizes with MCP-1 corresponds to the regular-spiking basket cells and is co-responsible for the perisomatic inhibition of principal pyramidal neurons. Previous studies have demonstrated that MCP-1 can alter the electric properties of neurons and a tonic function for this molecule has been postulated. As CCK-inhibitory neurons are affected in mood disorders, whether the expression of MCP-1 was maintained in humans could be part of the link between inflammatory responses and observed changes in mood state. [ABSTRACT FROM AUTHOR]