Publications

All Publications


  • Differentiation and maturation of oligodendrocytes in human three-dimensional neural cultures NATURE NEUROSCIENCE Marton, R. M., Miura, Y., Sloan, S. A., Li, Q., Revah, O., Levy, R. J., Huguenard, J. R., Pasca, S. P. 2019; 22 (3): 484-+
  • Differentiation and maturation of oligodendrocytes in human three-dimensional neural cultures. Nature neuroscience Marton, R. M., Miura, Y., Sloan, S. A., Li, Q., Revah, O., Levy, R. J., Huguenard, J. R., Pașca, S. P. 2019

    Abstract

    Investigating human oligodendrogenesis and the interaction of oligodendrocytes with neurons and astrocytes would accelerate our understanding of the mechanisms underlying white matter disorders. However, this is challenging because of the limited accessibility of functional human brain tissue. Here, we developed a new differentiation method of human induced pluripotent stem cells to generate three-dimensional brain organoids that contain oligodendrocytes as well as neurons and astrocytes, called human oligodendrocyte spheroids. We found that oligodendrocyte lineage cells derived in human oligodendrocyte spheroids transitioned through developmental stages similar to primary human oligodendrocytes and that the migration of oligodendrocyte lineage cells and their susceptibility to lysolecithin exposure could be captured by live imaging. Moreover, their morphology changed as they matured over time in vitro and started myelinating neurons. We anticipate that this method can be used to study oligodendrocyte development, myelination, and interactions with other major cell types in the CNS.

    View details for PubMedID 30692691

  • Deoxycytidine and deoxythymidine treatment for thymidine kinase 2 deficiency. Annals of neurology Lopez-Gomez, C., Levy, R. J., Sanchez-Quintero, M. J., Juanola-Falgarona, M., Barca, E., Garcia-Diaz, B., Tadesse, S., Garone, C., Hirano, M. 2017

    Abstract

    Thymidine kinase 2 (TK2), a critical enzyme in the mitochondrial pyrimidine salvage pathway, is essential for mitochondrial DNA (mtDNA) maintenance. Mutations in the nuclear gene TK2 cause TK2 deficiency, which manifests predominantly in children as myopathy with mtDNA depletion. Molecular bypass therapy with the TK2 products, dCMP and dTMP, prolongs the lifespan of Tk2-deficient (Tk2(-/-) ) mice by 2-3 fold. Because we observed rapid catabolism of the deoxynucleoside monophosphates to deoxythymidine (dT) and deoxycytidine (dC), we hypothesized that: 1) deoxynucleosides might be the major active agents and 2) inhibition of deoxycytidine deamination might enhance dTMP+dCMP therapy.To test these hypotheses, we assessed two therapies in Tk2(-/-) mice: 1) dT+dC and 2) co-administration of the deaminase inhibitor, tetrahydrouridine (THU), with dTMP+dCMP.We observed that dC+dT delayed disease onset, prolonged lifespan of Tk2-deficient mice, and restored mtDNA copy number as well as respiratory chain enzyme activities and levels. In contrast, dCMP+dTMP+THU therapy decreased lifespan of Tk2(-/-) animals compared to dCMP+dTMP.Our studies demonstrate that deoxynucleoside substrate enhancement is a novel therapy, which may ameliorate TK2 deficiency in patients. This article is protected by copyright. All rights reserved.

    View details for DOI 10.1002/ana.24922

    View details for PubMedID 28318037

  • Deletion of Rapgef6, a candidate schizophrenia susceptibility gene, disrupts amygdala function in mice TRANSLATIONAL PSYCHIATRY Levy, R. J., Kvajo, M., Li, Y., Tsvetkov, E., Dong, W., Yoshikawa, Y., Kataoka, T., Bolshakov, V. Y., Karayiorgou, M., Gogos, J. A. 2015; 5

    Abstract

    In human genetic studies of schizophrenia, we uncovered copy-number variants in RAPGEF6 and RAPGEF2 genes. To discern the effects of RAPGEF6 deletion in humans, we investigated the behavior and neural functions of a mouse lacking Rapgef6. Rapgef6 deletion resulted in impaired amygdala function measured as reduced fear conditioning and anxiolysis. Hippocampal-dependent spatial memory and prefrontal cortex-dependent working memory tasks were intact. Neural activation measured by cFOS phosphorylation demonstrated a reduction in hippocampal and amygdala activation after fear conditioning, while neural morphology assessment uncovered reduced spine density and primary dendrite number in pyramidal neurons of the CA3 hippocampal region of knockout mice. Electrophysiological analysis showed enhanced long-term potentiation at cortico-amygdala synapses. Rapgef6 deletion mice were most impaired in hippocampal and amygdalar function, brain regions implicated in schizophrenia pathophysiology. The results provide a deeper understanding of the role of the amygdala in schizophrenia and suggest that RAPGEF6 may be a novel therapeutic target in schizophrenia.

    View details for DOI 10.1038/tp.2015.75

    View details for Web of Science ID 000367658600001

    View details for PubMedID 26057047

  • Long Survival in Patients With Leigh Syndrome and the m.10191T > C Mutation in MT-ND3: A Case Report and Review of the Literature JOURNAL OF CHILD NEUROLOGY Levy, R. J., Rios, P. G., Akman, H. O., Sciacco, M., De Vivo, D. C., DiMauro, S. 2014; 29 (10): NP105-NP110

    Abstract

    We report an unusual case of Leigh syndrome due to the m.10191T>C mutation in the complex I gene MT-ND3. This mutation has been associated with a spectrum of clinical phenotypes ranging from infant lethality to adult onset. Despite infantile onset and severe symptoms, our patient has survived to early adulthood because of a strict dietary regimen and parental care. This patient is an extreme example of the frequently prolonged course of Leigh syndrome due to this particular mutation.

    View details for DOI 10.1177/0883073813506783

    View details for Web of Science ID 000342823700005

    View details for PubMedID 24284231

  • Copy number variation and psychiatric disease risk. Methods in molecular biology (Clifton, N.J.) Levy, R. J., Xu, B., Gogos, J. A., Karayiorgou, M. 2012; 838: 97-113

    Abstract

    Psychiatric disorders are multifactorial in nature with complex genetic architecture. A number of recent studies, building upon earlier findings of copy number variants (CNVs) at the 22q11.2 locus, suggest that rare CNVs represent an important component of genetic heterogeneity in the etiology of complex psychiatric diseases, such as schizophrenia. De novo CNVs are found with higher frequency among sporadic cases, whereas inherited CNVs are enriched among familial cases. Despite substantial progress, a number of challenges remain, such as pinpointing causative relationships between specific gene(s) affected by CNVs and disease phenotypes as well as distinguishing abnormal structural mutations from neutral polymorphisms and establishing a clear association between individual pathogenic CNV and disease phenotypes.

    View details for DOI 10.1007/978-1-61779-507-7_4

    View details for PubMedID 22228008

  • Altered axonal targeting and short-term plasticity in the hippocampus of Disc1 mutant mice PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Kvajo, M., McKellar, H., Drew, L. J., Lepagnol-Bestel, A., Xiao, L., Levy, R. J., Blazeski, R., Arguello, P. A., Lacefield, C. O., Mason, C. A., Simonneau, M., O'Donnell, J. M., MacDermott, A. B., Karayiorgou, M., Gogos, J. A. 2011; 108 (49): E1349-E1358

    Abstract

    Carefully designed animal models of genetic risk factors are likely to aid our understanding of the pathogenesis of schizophrenia. Here, we study a mouse strain with a truncating lesion in the endogenous Disc1 ortholog designed to model the effects of a schizophrenia-predisposing mutation and offer a detailed account of the consequences that this mutation has on the development and function of a hippocampal circuit. We uncover widespread and cumulative cytoarchitectural alterations in the dentate gyrus during neonatal and adult neurogenesis, which include errors in axonal targeting and are accompanied by changes in short-term plasticity at the mossy fiber/CA3 circuit. We also provide evidence that cAMP levels are elevated as a result of the Disc1 mutation, leading to altered axonal targeting and dendritic growth. The identified structural alterations are, for the most part, not consistent with the growth-promoting and premature maturation effects inferred from previous RNAi-based Disc1 knockdown. Our results provide support to the notion that modest disturbances of neuronal connectivity and accompanying deficits in short-term synaptic dynamics is a general feature of schizophrenia-predisposing mutations.

    View details for DOI 10.1073/pnas.1114113108

    View details for Web of Science ID 000297683800012

    View details for PubMedID 22049344