M D Moltó

University of Valencia, Valenza, Valencia, Spain

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Publications (64)240.5 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Auditory hallucinations (AH) are clinical hallmarks of schizophrenia, however little is known about molecular genetics of these symptoms. In this study, gene expression profiling of postmortem brain samples from prefrontal cortex of schizophrenic patients without AH (SNA), patients with AH (SA) and control subjects were compared. Genome-wide expression analysis was conducted using samples of three individuals of each group and the Affymetrix GeneChip Human-Gene 1.0 ST-Array. This analysis identified the Axon Guidance pathway as one of the most differentially expressed network among SNA, SA and CNT. To confirm the transcriptome results, mRNA level quantification of seventeen genes involved in this pathway was performed in a larger sample. PLXNB1, SEMA3A, SEMA4D and SEM6C were upregulated in SNA or SA patients compared to controls. PLXNA1 and SEMA3D showed down-regulation in their expression in the patient's samples, but differences remained statistically significant between the SNA patients and controls. Differences between SNA and SA were found in PLXNB1 expression which is decreased in SA patients. This study strengthens the contribution of brain plasticity in pathophysiology of schizophrenia and shows that non-hallucinatory patients present more alterations in frontal regions than patients with hallucinations concerning neural plasticity. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.
    07/2015; 229(3). DOI:10.1016/j.psychres.2015.07.074
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    ABSTRACT: Friedreich's ataxia (FRDA), the most common inherited ataxia in the Caucasian population, is a multisystemic disease caused by a significant decrease in the frataxin level. To identify genes capable of modifying the severity of the symptoms of frataxin depletion, we performed a candidate genetic screen in a Drosophila RNAi-based model of FRDA. We found that genetic reduction in TOR Complex 1 (TORC1) signalling improves the impaired motor performance phenotype of FRDA model flies. Pharmacologic inhibition of TORC1 signalling by rapamycin also restored this phenotype and increased the lifespan and ATP levels. Furthermore, rapamycin reduced the altered levels of malondialdehyde + 4-hydroxyalkenals and total glutathione of the model flies. The rapamycin-mediated protection against oxidative stress is due in part to an increase in the transcription of antioxidant genes mediated by cap-n-collar (Drosophila ortholog of Nrf2). Our results suggest that autophagy is indeed necessary for the protective effect of rapamycin in hyperoxia. Rapamycin increased the survival and aconitase activity of model flies subjected to high oxidative insult, and this improvement was abolished by the autophagy inhibitor 3-methyladenine. These results point to the TORC1 pathway as a new potential therapeutic target for FRDA and as a guide to finding new promising molecules for disease treatment.
    PLoS ONE 07/2015; 10(7):e0132376. DOI:10.1371/journal.pone.0132376 · 3.23 Impact Factor

  • Studies in health technology and informatics 01/2015; 210:950.
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    ABSTRACT: Genome wide association studies (GWAS) has allowed the discovery of some interesting risk variants for schizophrenia (SCZ). However, this high-throughput approach presents some limitations, being the most important the necessity of highly restrictive statistical corrections as well as the loss of statistical power inherent to the use of a Single Nucleotide Polymorphism (SNP) analysis approach. These problems can be partially solved through the use of a polygenic approach. We performed a genotyping study in SCZ using 86 previously associated SNPs identified by GWAS of SCZ, bipolar disorder (BPD) and autistic spectrum disorder (ASD) patients. The sample consisted of 3063 independent cases with DSM-IV-TR diagnosis of SCZ and 2847 independent controls of European origin from Spain. A polygenic score analysis was also used to test the overall effect on the SCZ status. One SNP, rs12290811, located in the ODZ4 gene reached statistical significance (p = 1.7 × 10− 4, Allelic odds ratio = 1.21), a value very near to those reported in previous GWAS of BPD patients. In addition, 4 SNPs were close to the significant threshold: rs3850333, in the NRXN1 gene; rs6932590, at MHC; rs2314398, located in an intergenic region on chromosome 2; and rs1006737, in the CACNA1C gene. We also found that 74% of the studied SNPs showed the same tendency (risk or protection alleles) previously reported in the original GWAS (p < 0.001). Our data strengthen the polygenic component of susceptibility to SCZ. Our findings show ODZ4 as a risk gene for SCZ, emphasizing the existence of common vulnerability in psychosis.
    Schizophrenia Research 10/2014; 159(1). DOI:10.1016/j.schres.2014.07.004 · 3.92 Impact Factor

  • Schizophrenia Research 04/2014; 153:S319. DOI:10.1016/S0920-9964(14)70901-6 · 3.92 Impact Factor
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    ABSTRACT: NO is a pleiotropic signaling molecule and has an important role in cognition and emotion. In the brain, NO is produced by neuronal nitric oxide synthase (NOS-I, encoded by NOS1) coupled to the NMDA receptor via PDZ interactions; this protein-protein interaction is disrupted upon binding of NOS1 adapter protein (encoded by NOS1AP) to NOS-I. As both NOS1 and NOS1AP were associated with schizophrenia, we here investigated these genes in greater detail by genotyping new samples and conducting a meta-analysis of our own and published data. In doing so, we confirmed association of both genes with schizophrenia and found evidence for their interaction in increasing risk towards disease. Our strongest finding was the NOS1 promoter SNP rs41279104, yielding an odds ratio of 1.29 in the meta-analysis. As findings from heterologous cell systems have suggested that the risk allele decreases gene expression, we studied the effect of the variant on NOS1 expression in human post-mortem brain samples and found that the risk allele significantly decreases expression of NOS1 in the prefrontal cortex. Bioinformatic analyses suggest that this might be due the replacement of six transcription factor binding sites by two new binding sites as a consequence of proxy SNPs. Taken together, our data argue that genetic variance in NOS1 resulting in lower prefrontal brain expression of this gene contributes to schizophrenia liability, and that NOS1 interacts with NOS1AP in doing so. The NOS1-NOS1AP PDZ interface may thus well constitute a novel target for small molecules in at least some forms of schizophrenia.
    European neuropsychopharmacology: the journal of the European College of Neuropsychopharmacology 09/2013; 24(1). DOI:10.1016/j.euroneuro.2013.09.005 · 4.37 Impact Factor
  • Javier Gilabert-Juan · Juan Nacher · Julio Sanjuán · María Dolores Moltó ·
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    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).
    09/2013; 210(3). DOI:10.1016/j.psychres.2013.09.001
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    ABSTRACT: Demyelinating disorders such as leukodystrophies and multiple sclerosis are neurodegenerative diseases characterized by the progressive loss of myelin that may lead toward a chronic demyelination of the brain's white matter, impairing normal axonal conduction velocity and ultimately causing neurodegeneration. Current treatments modifying the pathological mechanisms are capable of ameliorating the disease; however, frequently, these therapies are not sufficient to repress the progressive demyelination into a chronic condition and permanent loss of function. To this end, we analyzed the effect that bone marrow-derived mesenchymal stromal cell (BM-MSC) grafts exert in a chronically demyelinated mouse brain. As a result, oligodendrocyte progenitors were recruited surrounding the graft due to the expression of various trophic signals by the grafted MSCs. Although there was no significant reaction in the non-grafted side, in the grafted regions oligodendrocyte progenitors were detected. These progenitors were derived from the nearby tissue as well as from the neurogenic niches, including the subependymal zone and dentate gyrus. Once near the graft site, the cells matured to myelinating oligodendrocytes. Finally, electrophysiological studies demonstrated that axonal conduction velocity was significantly increased in the grafted side of the fimbria. In conclusion, we demonstrate here that in chronic demyelinated white matter, BM-MSC transplantation activates oligodendrocyte progenitors and induces remyelination in the tissue surrounding the stem cell graft.
    Cell Death & Disease 08/2013; 4(8):e779. DOI:10.1038/cddis.2013.304 · 5.01 Impact Factor
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    ABSTRACT: Both alterations in neurodevelopment and aversive experiences during childhood and adolescence seem important risk factors for schizophrenia. Animal models reproducing these alterations mimic some of the symptoms, constituting a valid approach to study the etiopathology of this disorder. Among these models, the perinatal injection of N-methyl-d-aspartate receptor antagonists and the postweaning social isolation rearing are among the most widely used. Our aim is to combine them in a "double hit" model, which should produce a wider spectrum of alterations. Lister Hooded rats have been subjected to a single injection of MK-801 at postnatal day 7 and socially isolated from postweaning to adulthood. These animals presented increased body weight gain and volume reductions in their medial prefrontal cortex (mPFC) and hippocampus. They also showed an increased number of activated pyramidal neurons and alterations in the numbers of parvalbumin and calbindin expressing interneurons in the mPFC. The expressions of the polysialylated form of the neural cell adhesion molecule and GAD67 are decreased in the mPFC. The mRNA level of calbindin was decreased, while that of calretinin was increased in the mPFC. The mRNA level of ERbB4, a gene associated to schizophrenia, were also altered in this region. All these structural and neurochemical alterations, specially in cortical inhibitory circuits, are similar to those found in schizophrenic patients and are more numerous than in each of the single models. Consequently, the present "double hit" model may be a better tool to study the neurobiological basis of schizophrenia and to explore new therapeutic approaches .
    Neurobiology of Disease 07/2013; 59. DOI:10.1016/j.nbd.2013.07.008 · 5.08 Impact Factor
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    ABSTRACT: Friedreich's ataxia (FRDA), the most common inherited ataxia, is a neurodegenerative disease caused by a reduction in the levels of the mitochondrial protein frataxin, the function of which remains a controversial matter. Several therapeutic approaches are being developed to increase frataxin expression and reduce the intramitochondrial iron aggregates and oxidative damage found in this disease. In this study, we tested separately the response of a Drosophila RNAi model of FRDA (Llorens et al., 2007) to treatment with the iron chelator Deferiprone (DFP) and the antioxidant Idebenone (IDE), which are both in clinical trials. The FRDA flies have a shortened life span and impaired motor coordination, and these phenotypes are more pronounced in oxidative stress conditions. In addition, under hyperoxia, the activity of the mitochondrial enzyme aconitase is strongly reduced in the FRDA flies. This study reports that DFP and IDE improve the life span and motor ability of frataxin-depleted flies. We show that DFP eliminates the excess of labile iron in the mitochondria and thus prevents the toxicity induced by iron accumulation. IDE treatment rescues aconitase activity in hyperoxic conditions. These results validate the use of our Drosophila model of FRDA to screen for therapeutic molecules to treat this disease.
    Gene 03/2013; 521(2). DOI:10.1016/j.gene.2013.02.049 · 2.14 Impact Factor
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    ABSTRACT: Chronic stress in experimental animals induces dendritic atrophy and decreases spine density in principal neurons of the medial prefrontal cortex (mPFC). This structural plasticity may play a neuroprotective role and underlie stress-induced behavioral changes. Different evidences indicate that the prefrontocortical GABA system is also altered by stress and in major depression patients. In the amygdala, chronic stress induces dendritic remodeling both in principal neurons and in interneurons. However, it is not known whether similar structural changes occur in mPFC interneurons. The polysialylated form of the neural cell adhesion molecule (PSA-NCAM) may mediate these changes, because it is known to influence the dendritic organization of adult cortical interneurons. We have analyzed the dendritic arborization and spine density of mPFC interneurons in adult mice after 21 days of restraint stress and have found dendritic hypertrophy in a subpopulation of interneurons identified mainly as Martinotti cells. This aversive experience also decreases the number of glutamate decarboxylase enzyme, 67 kDa isoform (GAD67) expressing somata, without affecting different parameters related to apoptosis, but does not alter the number of interneurons expressing PSA-NCAM. Quantitative retrotranscription-polymerase chain reaction (qRT-PCR) analysis of genes related to general and inhibitory neurotransmission and of PSA synthesizing enzymes reveals increases in the expression of NCAM, synaptophysin and GABA(A)α1. Together these results show that mPFC inhibitory networks are affected by chronic stress and suggest that structural plasticity may be an important feature of stress-related psychiatric disorders where this cortical region, specially their GABAergic system, is altered.
    Brain Structure and Function 11/2012; 218(6). DOI:10.1007/s00429-012-0479-1 · 5.62 Impact Factor

  • Schizophrenia Research 04/2012; 136:S133. DOI:10.1016/S0920-9964(12)70430-9 · 3.92 Impact Factor

  • Schizophrenia Research 04/2012; 136:S316. DOI:10.1016/S0920-9964(12)70932-5 · 3.92 Impact Factor
  • Javier Gilabert-Juan · Maria Dolores Moltó · Juan Nacher ·
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    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.
    Brain research 02/2012; 1448:129-36. DOI:10.1016/j.brainres.2012.01.073 · 2.84 Impact Factor
  • J. Sanjuan · J. Costas · M. D. Molto ·

    European Psychiatry 12/2011; 26:2054-2054. DOI:10.1016/S0924-9338(11)73757-9 · 3.44 Impact Factor
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    ABSTRACT: Chronic stress in experimental animals, one of the most accepted models of chronic anxiety and depression, induces structural remodeling of principal neurons in the amygdala and increases its excitation by reducing inhibitory tone. These changes may be mediated by the polysialylated form of the neural cell adhesion molecule (PSA-NCAM), a molecule related to neuronal structural plasticity and expressed by interneurons in the adult CNS, which is downregulated in the amygdala after chronic stress. We have analyzed the amygdala of adult mice after 21 days of restraint stress, studying with qRT-PCR the expression of genes related to general and inhibitory neurotransmission, and of PSA synthesizing enzymes. The expression of GAD67, synaptophysin and PSA-NCAM was also studied in specific amygdaloid nuclei using immunohistochemistry. We also analyzed dendritic arborization and spine density, and cell activity, monitoring c-Fos expression, in amygdaloid interneurons. At the mRNA level, the expression of GAD67 and of St8SiaII was significantly reduced. At the protein level there was an overall reduction in the expression of GAD67, synaptophysin and PSA-NCAM, but significant changes were only detected in specific amygdaloid regions. Chronic stress did not affect dendritic spine density, but reduced dendritic arborization in interneurons of the lateral and basolateral amygdala. These results indicate that chronic stress modulates inhibitory neurotransmission in the amygdala by regulating the expression of molecules involved in this process and by promoting the structural remodeling of interneurons. The addition of PSA to NCAM by St8SiaII may be involved in these changes.
    Experimental Neurology 07/2011; 232(1):33-40. DOI:10.1016/j.expneurol.2011.07.009 · 4.70 Impact Factor
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    ABSTRACT: Friedreich's ataxia (FA), the most frequent form of inherited ataxias in the Caucasian population, is caused by a reduced expression of frataxin, a highly conserved protein. Model organisms have contributed greatly in the efforts to decipher the function of frataxin; however, the precise function of this protein remains elusive. Overexpression studies are a useful approach to investigate the mechanistic actions of frataxin; however, the existing literature reports contradictory results. To further investigate the effect of frataxin overexpression, we analyzed the consequences of overexpressing human (FXN) and fly (FH) frataxins in Drosophila. We obtained transgenic flies that overexpressed human or fly frataxins in a general pattern and in different tissues using the UAS-GAL4 system. For both frataxins, we observed deleterious effects at the biochemical, histological and behavioral levels. Oxidative stress is a relevant factor in the frataxin overexpression phenotypes. Systemic frataxin overexpression reduces Drosophila viability and impairs the normal embryonic development of muscle and the peripheral nervous system. A reduction in the level of aconitase activity and a decrease in the level of NDUF3 were also observed in the transgenic flies that overexpressed frataxin. Frataxin overexpression in the nervous system reduces life span, impairs locomotor ability and causes brain degeneration. Frataxin aggregation and a misfolding of this protein have been shown not to be the mechanism that is responsible for the phenotypes that have been observed. Nevertheless, the expression of human frataxin rescues the aconitase activity in the fh knockdown mutant. Our results provide in vivo evidence of a functional equivalence for human and fly frataxins and indicate that the control of frataxin expression is important for treatments that aim to increase frataxin levels.
    PLoS ONE 07/2011; 6(7):e21017. DOI:10.1371/journal.pone.0021017 · 3.23 Impact Factor
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    ABSTRACT: Genetic studies on human personality have provided little satisfactory results to date mainly because of the complexity of this trait. Neonatal temperament using observational measures is an alternative phenotype to approach genetics to human behavior. An association study was conducted on 117 Caucasian newborns. Their temperament was evaluated using the Neonatal Behavior Assessment Scale 48 h after birth. Thirteen polymorphisms in the SLC6A4, DRD4 and TFAP2B genes were genotyped. Linear regression was performed to analyze data, and Bonferroni correction was applied. To check the functional effect of the TFAP2B Indel Intron 2 polymorphism, reporter gene luciferase assays using a mouse cortical neural progenitor cell line and quantitative polymerase chain reaction (qPCR) studies in human post-mortem brain samples were performed. A significant association was found between 5-HTTLPR, 5-HTTLPR + rs25531 and TFAP2B Indel Intron 2 with Range of State cluster as well as an interaction between rs25531 and TFAP2B Indel Intron 2 with Range of State. DRD4 variable number tandem repeat exon 3 was associated with orientation. A 30% increase in the luciferase levels of the TFAP2B 5-repeat alleles compared with the 6-repeat alleles (P-value = 0.03) was found using the pGL3 promoter vector. The qPCR experiments showed the same trend as the in vitro studies, although no significant results were obtained. This study supports a role of the SLC6A4, DRD4 and TFAP2B genes in the temperament, including a gene-gene interaction between SLC6A4 and TFAP2B. It also provides evidence about an effect of the TFAP2B polymorphism in TFAP2B gene transcription.
    Genes Brain and Behavior 04/2011; 10(5):570-8. DOI:10.1111/j.1601-183X.2011.00696.x · 3.66 Impact Factor

  • Psychiatry Research 03/2011; 186(1):153-4. DOI:10.1016/j.psychres.2010.07.005 · 2.47 Impact Factor
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    ABSTRACT: Friedreich’s ataxia (FRDA) is an autosomal recessive form of ataxia produced by a defi cient expression of the mitochondrial protein frataxin. Although demyelination has been described in post-mortem analysis of FRDA patients and in FRDA murine models, little is known about a possible glial dysfunction in FRDA neuropathology. In order to elucidate this aspect in Drosophila, frataxin was downregulated in glial cells using the pan-glial Repo-GAL4 driver and the established RNAi lines for targeted suppression of frataxin. We have found that specific loss of frataxin in glial cells shortens lifespan, increases sensitivity to oxidative insult, impairs locomotor activity and produces degeneration in the Drosophila brain along with the accumulation of lipid droplets in glial cells. To be able to study lipid dysfunction in reduced frataxin background, the ubiquitous daughterless driver line was used for RNAi expression. We found that a reduction of frataxin expression compromised lipid homeostasis at two different levels: increasing the total amount of lipids and enhancing the generation of peroxyl radicals. Interestingly, co-expression of glial lazarillo, a Drosophila apolipoprotein D ortholog, shows a strong protective effect against the loss of frataxin phenotype, mainly by reducing the lipid peroxidation level. Our results clearly identify glial cells as an important element of the frataxin phenotype. Moreover, we could show that lipid dysregulation is a significant factor for FRDA pathology identifying lipid peroxides as a primary cause of the symptoms.
    2010 European Drosophila Neurobiology Meeting; 12/2010

Publication Stats

2k Citations
240.50 Total Impact Points


  • 1987-2015
    • University of Valencia
      • Department of Genetics
      Valenza, Valencia, Spain
  • 2013
    • Fundación de Investigación del Hospital Clínico Universitario de Valencia INCLIVA
      Valenza, Valencia, Spain
  • 2011-2012
    • Centro de Investigación Biomedica En Red del Área de Salud Mental
      Madrid, Madrid, Spain
  • 2009
    • Instituto de Biomedicina
      Caracas, Capital, Venezuela
  • 2007
    • Universität Regensburg
      • Institute of Zoology
      Ratisbon, Bavaria, Germany
  • 1996
    • Baylor College of Medicine
      • Department of Neurology
      Houston, Texas, United States
  • 1994
    • Hospital Universitari i Politècnic la Fe
      • Department of Neurology
      Valenza, Valencia, Spain