Institute Investigaciones Biomedicas Of Barcelona

Barcelona, Spain

Institute Investigaciones Biomedicas Of Barcelona

Barcelona, Spain
Time filter
Source Type

Jimenez-Sanchez L.,Institute Investigaciones Biomedicas Of Barcelona | Jimenez-Sanchez L.,Research Center Biomedica En Red Of Salud Mental Cibersam | Castane A.,Institute Investigaciones Biomedicas Of Barcelona | Castane A.,Research Center Biomedica En Red Of Salud Mental Cibersam | And 15 more authors.
Cerebral Cortex | Year: 2016

Although deep brain stimulation (DBS) has been used with success in treatment-resistant depression, little is known about its mechanism of action. We examined the antidepressant-like activity of short (1 h) DBS applied to the infralimbic prefrontal cortex in the forced swim test (FST) and the novelty-suppressed feeding test (NSFT). We also used in vivo microdialysis to evaluate the release of glutamate, γ-aminobutyric acid, serotonin, dopamine, and noradrenaline in the prefrontal cortex and c-Fos immunohistochemistry to determine the brain regions activated by DBS. One hour of DBS of the infralimbic prefrontal cortex has antidepressant-like effects in FST and NSFT, and increases prefrontal efflux of glutamate, which would activate AMPA receptors (AMPARs). This effect is specific of the infralimbic area since it is not observed after DBS of the prelimbic subregion. The activation of prefrontal AMPARs would result in a stimulation of prefrontal output to the brainstem, thus increasing serotonin, dopamine, and noradrenaline in the prefrontal cortex. Further, the activation of prefrontal AMPARs is necessary and sufficient condition for the antidepressant response of 1 h DBS. © 2015 The Author. Published by Oxford University Press. All rights reserved.

Romon T.,Institute Investigaciones Biomedicas Of Barcelona | Romon T.,Research Center Biomedica En Red Of Salud Mental Cibersam | Mengod G.,Institute Investigaciones Biomedicas Of Barcelona | Mengod G.,CIBER ISCIII | And 2 more authors.
Psychopharmacology | Year: 2011

Rationale A reduction of GABAergic markers in postmortem tissue is consistently found in schizophrenia. This is generally mediated by a decreased expression of the calcium-binding protein, parvalbumin (PV), and the 67-kDa isoform of the GABA synthesizing enzyme glutamic acid decarboxylase (GAD 67). Similar reductions of PV or GAD 67 are observed after repeated exposure to N-methyl-D-aspartate (NMDA) receptor antagonists but less attention has been paid to what occurs after their acute administration. Objectives Here, we have used in situ hybridization to examine the expression of PV and GAD 67 mRNAs at 4 h and 24 h after an acute administration of MK-801 (1 mg/kg). Results Four hours after MK-801, the expression of PV mRNA decreased only in dentate gyrus of the hippocampus. Twenty four hours after this treatment, a reduction of the levels of PV mRNA was found in the medial prefrontal, orbitofrontal and entorhinal cortices, hippocampus and the basolateral nucleus of the amygdala. In contrast, no changes in the expression of GAD 67 were observed in any of the brain regions examined. Interestingly, the reduction in PV mRNA expression is observed in discrete corticolimbic subregions that have been implicated in schizophrenia, which is coincident with changes observed in postmortem tissue of schizophrenia brain. Conclusions These findings indicate that acute administration of a NMDA antagonist delineate a pattern of changes in GABAergic markers different from those observed in postmortem tissue in schizophrenia inasmuch as only deficits in parvalbumin (but not GAD 67) were seen. © 2011 Springer-Verlag.

Lopez-Gil X.,Institute Investigaciones Biomedicas Of Barcelona | Lopez-Gil X.,Research Center Biomedica En Red Of Salud Mental Cibersam | Artigas F.,Institute Investigaciones Biomedicas Of Barcelona | Artigas F.,Research Center Biomedica En Red Of Salud Mental Cibersam | And 2 more authors.
Current Pharmaceutical Design | Year: 2010

The systemic administration of noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonists has been considered as a pharmacological model of schizophrenia. In the present work, we used in vivo microdialysis to examine: first, the effects of MK-801, on the efflux of glutamate and serotonin (5-HT) in the medial prefrontal cortex (mPFC) of the rat; second, whether the MK-801-induced changes in the cortical efflux of both transmitters could be blocked by atypical (clozapine and olanzapine) and classical (haloperidol and chlorpromazine) antipsychotic drugs given intra-mPFC; and third, the role of local blockade of dopamine D2/D3/D4, serotonin 5-HT2A and α1-adrenergic receptors as well as agonism at dopamine D1/D5 and 5-HT1A receptors in the mPFC on the increased efflux of glutamate and 5-HT elicited by MK-801. The four antipsychotic drugs blocked the MK-801-induced increase in glutamate, whereas only clozapine and olanzapine were able to block the increased efflux of 5-HT. Furthermore, M100907 (5-HT2A antagonist), BAY x 3702 (5-HT1A agonist) and prazosin (α1-adrenergic antagonist) blocked the MK-801-induced increase of 5-HT and glutamate in the mPFC. In contrast, raclopride (D2/D3 antagonist) and L-745,870 (D4 antagonist) were able to prevent the increased efflux of glutamate (but not that of 5-HT) elicited by MK-801. SKF-38393 (dopamine D1/D5 agonist) also prevented the MK-801-induced increase of glutamate in the mPFC, but the same effect on cortical 5-HT was reached only at the highest concentration tested. We suggest that the blockade of an exacerbated 5-HT release in the mPFC induced by NMDA antagonists can be a characteristic of atypical antipsychotic drugs. Moreover, we propose that D 2/D3/D4 receptor antagonists would act predominantly on a subpopulation of GABAergic interneurons of the mPFC, thus enhancing cortical inhibition, which would prevent an excessive glutamatergic transmission. Dopamine D1/D5 agonists would further stimulate GABA release from other subpopulation of interneurons controlling cortical output to the dorsal raphe nucleus. Atypical antipsychotic drugs might further act upon 5-HT2A, 5-HT1A and α1- adrenoceptors present in pyramidal cells (including those projecting to the dorsal raphe nucleus), which would directly inhibit an excessive excitability of these cells. © 2010 Bentham Science Publishers Ltd.

Mlguez D.G.,Institute Biologla Molecular Of Barcelona | Mlguez D.G.,Autonomous University of Madrid | Gil-Guinon E.,Institute Biologla Molecular Of Barcelona | Pons S.,Institute Biologla Molecular Of Barcelona | And 2 more authors.
Journal of Cell Science | Year: 2013

The transforming growth factor beta (TGF-b) pathway plays key roles in development and cancer. TGF-b signaling converges on the Smad2 and Smad3 effectors, which can either cooperate or antagonize to regulate their transcriptional targets. Here we performed in vivo and in silico experiments to study how such cooperativity and antagonism might function during neurogenesis. In vivo electroporation experiments in the chick embryo neural tube show that Smad2 and Smad3 cooperate to promote neurogenesis, as well as the transcription of Smad3-specific targets. Knockdown of Smad2 enhances neurogenesis and the transcription of Smad3-specific targets. A mathematical model of the TGF-b pathway fits the experimental results and predicts that the proportions of the three different trimeric complexes formed dictates the transcriptional responses of the R-Smad proteins. As such, Smad2 targets are activated solely by the Smad2-Smad2-Smad4 complex, whereas Smad3 targets are activated both by Smad2-Smad3-Smad4 and Smad3-Smad3-Smad4 trimers. We have modeled the Smad responses onto arbitrary genes and propose that this mechanism might be extended to additional activities of TGF-b in development and disease. © 2013. Published by The Company of Biologists Ltd.

Veny M.,Institute Investigaciones Biomedicas Of Barcelona | Esteller M.,CIBER ISCIII | Ricart E.,CIBER ISCIII | PiquE J.M.,CIBER ISCIII | And 2 more authors.
Alimentary Pharmacology and Therapeutics | Year: 2010

Aliment Pharmacol Ther 31, 561-572 SummaryBackground Th1 and Th17 cells have been implicated in Crohn's disease (CD) pathophysiology and may play a role in disease persistence. Aim To determine Th1 and Th17 responses in intestine and peripheral blood of early (<32 weeks since initial symptoms) and late (>2 years) CD patients. Methods Cytokine mRNA in intestinal biopsies was determined by RT-PCR. Cytokine concentration in culture was measured by ELISA and cytokine-producing cells were identified by intracellular staining. Results The inflamed mucosa showed significantly increased IL-17 mRNA levels compared with non-inflamed areas, both in early and late CD patients. However, only patients with late (n = 12), but not early (n = 9), active disease showed increased IL-17 production, as well as a significantly higher percentage of IL-17+CD4+ cells in blood, compared with controls (n = 12) or patients in remission (n = 13). Moreover, cultured peripheral CD4 + cells from late active CD patients presented significantly higher percentages of IL-17+, IL-22+ and IFN-γ+ and a significantly increased production of IL-17 and IL-22, but not IFN-γ+. Conclusions Increased IL-17 gene transcription is common to early and late CD mucosa. However, exacerbated Th17 responses in the peripheral blood appear only in late disease. We propose that this population may constitute a mechanism of perpetuating the disease. © 2010 Blackwell Publishing Ltd.

Jimenez-Sanchez L.,Institute Investigaciones Biomedicas Of Barcelona | Jimenez-Sanchez L.,Research Center Biomedica En Red Of Salud Mental Cibersam | Jimenez-Sanchez L.,Institute dInvestigacions Biomediques August Pi i Sunyer IDIBAPS | Campa L.,Institute Investigaciones Biomedicas Of Barcelona | And 6 more authors.
Neuropsychopharmacology | Year: 2014

Paradoxically, N-methyl-D-aspartate (NMDA) receptor antagonists are used to model certain aspects of schizophrenia as well as to treat refractory depression. However, the role of different subunits of the NMDA receptor in both conditions is poorly understood. Here we used biochemical and behavioral readouts to examine the in vivo prefrontal efflux of serotonin and glutamate as well as the stereotypical behavior and the antidepressant-like activity in the forced swim test elicited by antagonists selective for the GluN2A (NVP-AAM077) and GluN2B (Ro 25-6981) subunits. The effects of the non-subunit selective antagonist, MK-801; were also studied for comparison. The administration of MK-801 dose dependently increased the prefrontal efflux of serotonin and glutamate and markedly increased the stereotypy scores. NVP-AAM077 also increased the efflux of serotonin and glutamate, but without the induction of stereotypies. In contrast, Ro 25-6981 did not change any of the biochemical and behavioral parameters tested. Interestingly, the administration of NVP-AAM077 and Ro 25-6981 alone elicited antidepressant-like activity in the forced swim test, in contrast to the combination of both compounds that evoked marked stereotypies. Our interpretation of the results is that both GluN2A and GluN2B subunits are needed to induce stereotypies, which might be suggestive of potential psychotomimetic effects in humans, but the antagonism of only one of these subunits is sufficient to evoke an antidepressant response. We also propose that GluN2A receptor antagonists could have potential antidepressant activity in the absence of potential psychotomimetic effects.

Ventura M.,University of Barcelona | Mateo F.,University of Barcelona | Serratosa J.,Institute Investigaciones Biomedicas Of Barcelona | Salaet I.,University of Barcelona | And 3 more authors.
International Journal of Biochemistry and Cell Biology | Year: 2010

Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is considered a housekeeping glycolitic enzyme that recently has been implicated in cell signaling. Under apoptotic stresses, cells activate nitric oxide formation leading to S-nitrosylation of GAPDH that binds to Siah and translocates to the nucleus. The GAPDH-Siah interaction depends on the integrity of lysine 227 in human GAPDH, being the mutant K227A unable to associate with Siah. As lysine residues are susceptible to be modified by acetylation, we aimed to analyze whether acetylation could mediate transport of GAPDH from cytoplasm to the nucleus. We observed that the acetyltransferase P300/CBP-associated factor (PCAF) interacts with and acetylates GAPDH. We also found that over-expression of PCAF induces the nuclear translocation of GAPDH and that for this translocation its intact acetylase activity is needed. Finally, the knocking down of PCAF reduces nuclear translocation of GAPDH induced by apoptotic stimuli. By spot mapping analysis we first identified Lys 117 and 251 as the putative GAPDH residues that could be acetylated by PCAF. We further demonstrated that both Lys were necessary but not sufficient for nuclear translocation of GAPDH after apoptotic stimulation. Finally, we identified Lys 227 as a third GAPDH residue whose acetylation is needed for its transport from cytoplasm to the nucleus. Thus, results reported here indicate that nuclear translocation of GAPDH is mediated by acetylation of three specific Lys residues (117, 227 and 251 in human cells). Our results also revealed that PCAF participates in the GAPDH acetylation that leads to its translocation to the nucleus. © 2010 Elsevier Ltd.

Herrera A.,Institute Investigaciones Biomedicas Of Barcelona | Saade M.,Institute Biologi A Molecular Of Barcelona | Menendez A.,Institute Investigaciones Biomedicas Of Barcelona | Marti E.,Institute Biologi A Molecular Of Barcelona | And 2 more authors.
Nature Communications | Year: 2014

β-Catenin mediates the canonical Wnt pathway by stimulating Tcf-dependent transcription and also associates to N-cadherin at the apical complex (AC) of neuroblasts. Here, we show that while β-catenin activity is required to form the AC and to maintain the cell polarity, oncogenic mutations that render stable forms of β-catenin (sβ-catenin) maintain the stemness of neuroblasts, inhibiting their differentiation and provoking aberrant growth. In examining the transcriptional and structural roles of β-catenin, we find that while β-catenin/Tcf transcriptional activity induces atypical protein kinase C (aPKC) expression, an alternative effect of β-catenin restricts aPKC to the apical pole of neuroepithelial cells. In agreement, we show that a constitutively active form of aPKC reproduces the neuroepithelial aberrations induced by β-catenin. Therefore, we conclude that β-catenin controls the cell fate and polarity of the neuroblasts through the expression and localization of aPKC. © 2014 Macmillan Publishers Limited.

Barzi M.,Institute Investigaciones Biomedicas Of Barcelona | Kostrz D.,Institute Investigaciones Biomedicas Of Barcelona | Menendez A.,Institute Investigaciones Biomedicas Of Barcelona | Pons S.,Institute Investigaciones Biomedicas Of Barcelona
Journal of Biological Chemistry | Year: 2011

Proliferation of cerebellar granular neuronal precursors (CGNPs) is mediated by Sonic Hedgehog (Shh), which activates the Patched and Smoothened (Smo) receptor complex. Although its protein sequence suggests that Smo is a G protein coupled receptor (GPCR), the evidence that this receptor utilizes heterotrimeric G proteins as downstream effectors is controversial. In Drosophila, Gαi is required for Hedgehog (Hh) activity, but the involvement of heterotrimeric G proteins in vertebrate Shh signaling has not yet been established. Here, we show that Shh-induced proliferation of rat CGNPs is enhanced strongly by the expression of the active forms of Gαi/o proteins (Gαi1, Gαi2, Gαi3, and Gαo) but not by members of another class (Gα12) of heterotrimeric G proteins. Additionally, the mRNAs of these different Gαi members display specific expression patterns in the developing cerebellum; only Gαi2 and Gαi3 are substantially expressed in the outer external granular layer, where CGNPs proliferate. Consistent with this, Shh-induced proliferation of CGNPs is reduced significantly by knockdowns of Gαi2 and Gαi3 but not by silencing of other members of the Gαi/o class. Finally, our results demonstrate that Gαi2 and Gαi3 locate to the primary cilium when expressed in CGNP cultures. In summary, we conclude that the proliferative effects of Shh on CGNPs are mediated by the combined activity of Gαi2 and Gαi3 proteins. © 2011 by The American Society for Biochemistry and Molecular Biology, Inc.

Adell A.,Institute Investigaciones Biomedicas Of Barcelona | Adell A.,Research Center Biomedica En Red Of Salud Mental Cibersam | Jimenez-Sanchez L.,Institute Investigaciones Biomedicas Of Barcelona | Jimenez-Sanchez L.,Research Center Biomedica En Red Of Salud Mental Cibersam | And 4 more authors.
Schizophrenia Bulletin | Year: 2012

Several genetic, neurodevelopmental, and pharmacological animal models of schizophrenia have been established. This short review examines the validity of one of the most used pharmacological model of the illness, ie, the acute administration of N-methyl-D-aspartate (NMDA) receptor antagonists in rodents. In some cases, data on chronic or prenatal NMDA receptor antagonist exposure have been introduced for comparison. The face validity of acute NMDA receptor blockade is granted inasmuch as hyperlocomotion and stereotypies induced by phencyclidine, ketamine, and MK-801 are regarded as a surrogate for the positive symptoms of schizophrenia. In addition, the loss of parvalbumin-containing cells (which is one of the most compelling finding in postmortem schizophrenia brain) following NMDA receptor blockade adds construct validity to this model. However, the lack of changes in glutamic acid decarboxylase (GAD 67) is at variance with human studies. It is possible that changes in GAD67 are more reflective of the neurodevelopmental condition of schizophrenia. Finally, the model also has predictive validity, in that its behavioral and transmitter activation in rodents are responsive to antipsychotic treatment. Overall, although not devoid of drawbacks, the acute administration of NMDA receptor antagonists can be considered as a good model of schizophrenia bearing a satisfactory degree of validity. © 2011 The Author.

Loading Institute Investigaciones Biomedicas Of Barcelona collaborators
Loading Institute Investigaciones Biomedicas Of Barcelona collaborators