Identification of neural oscillations and epileptiform changes in human brain organoids.

Adult Benzothiazoles / pharmacology Brain / growth & development Calcium Signaling Child, Preschool Epilepsy / diagnostic imaging Female Humans Induced Pluripotent Stem Cells Methyl-CpG-Binding Protein 2 / genetics Nerve Net / physiopathology Neurogenesis / genetics Neuroimaging Neurons Rett Syndrome / diagnostic imaging Single-Cell Analysis Synapses Toluene / analogs & derivatives Transcriptome

Journal

Nature neuroscience
ISSN: 1546-1726
Titre abrégé: Nat Neurosci
Pays: United States
ID NLM: 9809671

Informations de publication

Date de publication:
10 2021
Historique:
received: 29 08 2019
accepted: 08 07 2021
pubmed: 25 8 2021
medline: 9 10 2021
entrez: 24 8 2021
Statut: ppublish

Résumé

Brain organoids represent a powerful tool for studying human neurological diseases, particularly those that affect brain growth and structure. However, many diseases manifest with clear evidence of physiological and network abnormality in the absence of anatomical changes, raising the question of whether organoids possess sufficient neural network complexity to model these conditions. Here, we explore the network-level functions of brain organoids using calcium sensor imaging and extracellular recording approaches that together reveal the existence of complex network dynamics reminiscent of intact brain preparations. We demonstrate highly abnormal and epileptiform-like activity in organoids derived from induced pluripotent stem cells from individuals with Rett syndrome, accompanied by transcriptomic differences revealed by single-cell analyses. We also rescue key physiological activities with an unconventional neuroregulatory drug, pifithrin-α. Together, these findings provide an essential foundation for the utilization of brain organoids to study intact and disordered human brain network formation and illustrate their utility in therapeutic discovery.

Identifiants

DOI: 10.1038/s41593-021-00906-5 PMID: 34426698 PMC: PMC9070733
pubmed: 34426698
doi: 10.1038/s41593-021-00906-5
pii: 10.1038/s41593-021-00906-5
pmc: PMC9070733
mid: NIHMS1798064
doi:

Substances chimiques

Benzothiazoles 0
MECP2 protein, human 0
Methyl-CpG-Binding Protein 2 0
Toluene 3FPU23BG52
pifithrin D213B92S1Y

Types de publication

Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

1488-1500

Subventions

Organisme : NINDS NIH HHS
ID : R01 NS088571
Pays : United States
Organisme : NINDS NIH HHS
ID : R25 NS065723
Pays : United States
Organisme : NICHD NIH HHS
ID : R00 HD096105
Pays : United States
Organisme : NIGMS NIH HHS
ID : P01 GM099134
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS030549
Pays : United States
Organisme : NINDS NIH HHS
ID : K08 NS119747
Pays : United States
Organisme : NIA NIH HHS
ID : RF1 AG050474
Pays : United States
Organisme : NIDA NIH HHS
ID : R01 DA051897
Pays : United States
Organisme : NIMH NIH HHS
ID : R01 MH123922
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS089817
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS103788
Pays : United States
Organisme : NICHD NIH HHS
ID : P50 HD103557
Pays : United States
Organisme : NICHD NIH HHS
ID : U54 HD087101
Pays : United States
Organisme : NIMH NIH HHS
ID : R01 MH121521
Pays : United States
Organisme : NICHD NIH HHS
ID : K99 HD096105
Pays : United States

Commentaires et corrections

Type : CommentIn

Informations de copyright

© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.

Références

Di Lullo, E. & Kriegstein, A. R. The use of brain organoids to investigate neural development and disease. Nat. Rev. Neurosci. 18, 573–584 (2017).
pubmed: 28878372 pmcid: 5667942 doi: 10.1038/nrn.2017.107
Amin, N. D. & Pasca, S. P. Building models of brain disorders with three-dimensional organoids. Neuron 100, 389–405 (2018).
pubmed: 30359604 doi: 10.1016/j.neuron.2018.10.007
Qian, X., Song, H. & Ming, G. L. Brain organoids: advances, applications and challenges. Development 146, dev166074 (2019).
Rakic, P. Evolution of the neocortex: a perspective from developmental biology. Nat. Rev. Neurosci. 10, 724–735 (2009).
pubmed: 19763105 pmcid: 2913577 doi: 10.1038/nrn2719
Molnar, Z. et al. Evolution and development of the mammalian cerebral cortex. Brain Behav. Evol. 83, 126–139 (2014).
pubmed: 24776993 doi: 10.1159/000357753
van der Worp, H. B. et al. Can animal models of disease reliably inform human studies? PLoS Med. 7, e1000245 (2010).
pubmed: 20361020 pmcid: 2846855 doi: 10.1371/journal.pmed.1000245
Dawson, T. M., Golde, T. E. & Lagier-Tourenne, C. Animal models of neurodegenerative diseases. Nat. Neurosci. 21, 1370–1379 (2018).
pubmed: 30250265 pmcid: 6615039 doi: 10.1038/s41593-018-0236-8
Stam, C. J. Modern network science of neurological disorders. Nat. Rev. Neurosci. 15, 683–695 (2014).
pubmed: 25186238 doi: 10.1038/nrn3801
Palop, J. J. & Mucke, L. Network abnormalities and interneuron dysfunction in Alzheimer disease. Nat. Rev. Neurosci. 17, 777–792 (2016).
pubmed: 27829687 pmcid: 8162106 doi: 10.1038/nrn.2016.141
Sun, A. X. et al. Potassium channel dysfunction in human neuronal models of Angelman syndrome. Science 366, 1486–1492 (2019).
pubmed: 31857479 pmcid: 7735558 doi: 10.1126/science.aav5386
Trujillo, C. A. et al. Complex oscillatory waves emerging from cortical organoids model early human brain network development. Cell Stem Cell 25, 558–569 (2019).
pubmed: 31474560 pmcid: 6778040 doi: 10.1016/j.stem.2019.08.002
Buzsaki, G. & Wang, X. J. Mechanisms of gamma oscillations. Annu Rev. Neurosci. 35, 203–225 (2012).
pubmed: 22443509 pmcid: 4049541 doi: 10.1146/annurev-neuro-062111-150444
Headley, D. B. & Paré, D. Common oscillatory mechanisms across multiple memory systems. NPJ Sci. Learn. 2, 1 (2017).
Verret, L. et al. Inhibitory interneuron deficit links altered network activity and cognitive dysfunction in Alzheimer model. Cell 149, 708–721 (2012).
pubmed: 22541439 pmcid: 3375906 doi: 10.1016/j.cell.2012.02.046
Matsumoto, J. Y. et al. Network oscillations modulate interictal epileptiform spike rate during human memory. Brain 136, 2444–2456 (2013).
pubmed: 23803305 pmcid: 3722348 doi: 10.1093/brain/awt159
van Dellen, E. et al. Local polymorphic delta activity in cortical lesions causes global decreases in functional connectivity. Neuroimage 83, 524–532 (2013).
pubmed: 23769919 doi: 10.1016/j.neuroimage.2013.06.009
Watanabe, M. et al. Self-organized cerebral organoids with human-specific features predict effective drugs to combat Zika virus infection. Cell Rep. 21, 517–532 (2017).
pubmed: 29020636 pmcid: 5637483 doi: 10.1016/j.celrep.2017.09.047
Bagley, J. A., Reumann, D., Bian, S., Levi-Strauss, J. & Knoblich, J. A. Fused cerebral organoids model interactions between brain regions. Nat. Methods 14, 743–751 (2017).
pubmed: 28504681 pmcid: 5540177 doi: 10.1038/nmeth.4304
Birey, F. et al. Assembly of functionally integrated human forebrain spheroids. Nature 545, 54–59 (2017).
pubmed: 28445465 pmcid: 5805137 doi: 10.1038/nature22330
Xiang, Y. et al. Fusion of regionally specified hPSC-derived organoids models human brain development and interneuron migration. Cell Stem Cell 21, 383–398 (2017).
pubmed: 28757360 pmcid: 5720381 doi: 10.1016/j.stem.2017.07.007
Sakaguchi, H., et al. Self-organized synchronous calcium transients in a cultured human neural network derived from cerebral organoids. Stem Cell Reports 13, 458–473 (2019).
Lyst, M. J. & Bird, A. Rett syndrome: a complex disorder with simple roots. Nat. Rev. Genet. 16, 261–275 (2015).
pubmed: 25732612 doi: 10.1038/nrg3897
Garofalo, E. A., Drury, I. & Goldstein, G. W. EEG abnormalities aid diagnosis of Rett syndrome. Pediatr. Neurol. 4, 350–353 (1988).
pubmed: 3245872 doi: 10.1016/0887-8994(88)90081-1
Operto, F. F., Mazza, R., Pastorino, G. M. G., Verrotti, A. & Coppola, G. Epilepsy and genetic in Rett syndrome: a review. Brain Behav. 9, e01250 (2019).
pubmed: 30929312 pmcid: 6520293 doi: 10.1002/brb3.1250
Watanabe, M., et al. TGFβ superfamily signaling regulates the state of human stem cell pluripotency and competency to create telencephalic organoids. Preprint at bioRxiv, https://doi.org/10.1101/2019.12.13.875773 (2019).
Hendry, S. H., Schwark, H. D., Jones, E. G. & Yan, J. Numbers and proportions of GABA-immunoreactive neurons in different areas of monkey cerebral cortex. J. Neurosci. 7, 1503–1519 (1987).
pubmed: 3033170 pmcid: 6568832 doi: 10.1523/JNEUROSCI.07-05-01503.1987
Sahara, S., Yanagawa, Y., O’Leary, D. D. & Stevens, C. F. The fraction of cortical GABAergic neurons is constant from near the start of cortical neurogenesis to adulthood. J. Neurosci. 32, 4755–4761 (2012).
pubmed: 22492031 pmcid: 3325497 doi: 10.1523/JNEUROSCI.6412-11.2012
Ferando, I. & Mody, I. In vitro gamma oscillations following partial and complete ablation of delta subunit-containing GABA
pubmed: 25261782 doi: 10.1016/j.neuropharm.2014.09.010
Pnevmatikakis, E. A. et al. Simultaneous denoising, deconvolution and demixing of calcium imaging data. Neuron 89, 285–299 (2016).
pubmed: 26774160 pmcid: 4881387 doi: 10.1016/j.neuron.2015.11.037
Zhou, P., et al. Efficient and accurate extraction of in vivo calcium signals from microendoscopic video data. Elife 7, e28728 (2018).
Buzsaki, G. & Draguhn, A. Neuronal oscillations in cortical networks. Science 304, 1926–1929 (2004).
pubmed: 15218136 doi: 10.1126/science.1099745
Wang, D. D. & Kriegstein, A. R. GABA regulates excitatory synapse formation in the neocortex via NMDA receptor activation. J. Neurosci. 28, 5547–5558 (2008).
pubmed: 18495889 pmcid: 2684685 doi: 10.1523/JNEUROSCI.5599-07.2008
Wang, D. D. & Kriegstein, A. R. Blocking early GABA depolarization with bumetanide results in permanent alterations in cortical circuits and sensorimotor gating deficits. Cereb. Cortex 21, 574–587 (2011).
pubmed: 20624842 doi: 10.1093/cercor/bhq124
Leonard, H., Cobb, S. & Downs, J. Clinical and biological progress over 50 years in Rett syndrome. Nat. Rev. Neurol. 13, 37–51 (2017).
pubmed: 27934853 doi: 10.1038/nrneurol.2016.186
Mellios, N. et al. MeCP2-regulated miRNAs control early human neurogenesis through differential effects on ERK and AKT signaling. Mol. Psychiatry 23, 1051–1065 (2018).
pubmed: 28439102 doi: 10.1038/mp.2017.86
Armstrong, D. D., Dunn, K. & Antalffy, B. Decreased dendritic branching in frontal, motor and limbic cortex in Rett syndrome compared with trisomy 21. J. Neuropathol. Exp. Neurol. 57, 1013–1017 (1998).
pubmed: 9825937 doi: 10.1097/00005072-199811000-00003
Belichenko, P. V. et al. Widespread changes in dendritic and axonal morphology in Mecp2-mutant mouse models of Rett syndrome: evidence for disruption of neuronal networks. J. Comp. Neurol. 514, 240–258 (2009).
pubmed: 19296534 doi: 10.1002/cne.22009
Marchetto, M. C. et al. A model for neural development and treatment of Rett syndrome using human induced pluripotent stem cells. Cell 143, 527–539 (2010).
pubmed: 21074045 pmcid: 3003590 doi: 10.1016/j.cell.2010.10.016
Ohashi, M. et al. Loss of MECP2 leads to activation of P53 and neuronal senescence. Stem Cell Reports 10, 1453–1463 (2018).
pubmed: 29742391 pmcid: 5995366 doi: 10.1016/j.stemcr.2018.04.001
D’Haene, E. et al. A neuronal enhancer network upstream of MEF2C is compromised in patients with Rett-like characteristics. Hum. Mol. Genet. 28, 818–827 (2019).
pubmed: 30445463 doi: 10.1093/hmg/ddy393
Wang, J. et al. Novel MEF2C point mutations in Chinese patients with Rett (-like) syndrome or non-syndromic intellectual disability: insights into genotype-phenotype correlation. BMC Med. Genet. 19, 191 (2018).
pubmed: 30376817 pmcid: 6208086 doi: 10.1186/s12881-018-0699-1
Salpietro, V. et al. AMPA receptor GluA2 subunit defects are a cause of neurodevelopmental disorders. Nat. Commun. 10, 3094 (2019).
pubmed: 31300657 pmcid: 6626132 doi: 10.1038/s41467-019-10910-w
Huisman, S. et al. Phenotypes and genotypes in individuals with SMC1A variants. Am. J. Med. Genet. A 173, 2108–2125 (2017).
pubmed: 28548707 doi: 10.1002/ajmg.a.38279
Lopes, F. et al. Identification of novel genetic causes of Rett syndrome-like phenotypes. J. Med. Genet. 53, 190–199 (2016).
pubmed: 26740508 doi: 10.1136/jmedgenet-2015-103568
Oyang, E. L., Davidson, B. C., Lee, W. & Poon, M. M. Functional characterization of the dendritically localized mRNA neuronatin in hippocampal neurons. PLoS ONE 6, e24879 (2011).
pubmed: 21935485 pmcid: 3173491 doi: 10.1371/journal.pone.0024879
Sharma, J. et al. Neuronatin-mediated aberrant calcium signaling and endoplasmic reticulum stress underlie neuropathology in Lafora disease. J. Biol. Chem. 288, 9482–9490 (2013).
pubmed: 23408434 pmcid: 3611017 doi: 10.1074/jbc.M112.416180
Lu, H. et al. Loss and gain of MeCP2 cause similar hippocampal circuit dysfunction that is rescued by deep brain stimulation in a Rett syndrome mouse model. Neuron 91, 739–747 (2016).
pubmed: 27499081 pmcid: 5019177 doi: 10.1016/j.neuron.2016.07.018
Feldt Muldoon, S., Soltesz, I. & Cossart, R. Spatially clustered neuronal assemblies comprise the microstructure of synchrony in chronically epileptic networks. Proc. Natl Acad. Sci. USA 110, 3567–3572 (2013).
pubmed: 23401510 pmcid: 3587208 doi: 10.1073/pnas.1216958110
Bragin, A., Engel, J. Jr., Wilson, C. L., Fried, I. & Buzsaki, G. High-frequency oscillations in human brain. Hippocampus 9, 137–142 (1999).
pubmed: 10226774 doi: 10.1002/(SICI)1098-1063(1999)9:2<137::AID-HIPO5>3.0.CO;2-0
Bragin, A., Wilson, C. L., Almajano, J., Mody, I. & Engel, J. Jr. High-frequency oscillations after status epilepticus: epileptogenesis and seizure genesis. Epilepsia 45, 1017–1023 (2004).
pubmed: 15329064 doi: 10.1111/j.0013-9580.2004.17004.x
Ito-Ishida, A., Ure, K., Chen, H., Swann, J. W. & Zoghbi, H. Y. Loss of MeCP2 in parvalbumin-and somatostatin-expressing neurons in mice leads to distinct Rett syndrome-like phenotypes. Neuron 88, 651–658 (2015).
pubmed: 26590342 pmcid: 4656196 doi: 10.1016/j.neuron.2015.10.029
Krajnc, N. Management of epilepsy in patients with Rett syndrome: perspectives and considerations. Ther. Clin. Risk Manag. 11, 925–932 (2015).
pubmed: 26089674 pmcid: 4468994 doi: 10.2147/TCRM.S55896
Vignoli, A. et al. Effectiveness and tolerability of antiepileptic drugs in 104 girls with Rett syndrome. Epilepsy Behav. 66, 27–33 (2017).
pubmed: 27988477 doi: 10.1016/j.yebeh.2016.10.006
Squillaro, T. et al. Reduced expression of MECP2 affects cell commitment and maintenance in neurons by triggering senescence: new perspective for Rett syndrome. Mol. Biol. Cell 23, 1435–1445 (2012).
pubmed: 22357617 pmcid: 3327309 doi: 10.1091/mbc.e11-09-0784
Lee, B., Shin, D., Gross, S. P. & Cho, K. H. Combined positive and negative feedback allows modulation of neuronal oscillation frequency during sensory processing. Cell Rep. 25, 1548–1560 (2018).
pubmed: 30404009 doi: 10.1016/j.celrep.2018.10.029
Chen, G. et al. Distinct inhibitory circuits orchestrate cortical beta and gamma band oscillations. Neuron 96, 1403–1418 (2017).
pubmed: 29268099 pmcid: 5864125 doi: 10.1016/j.neuron.2017.11.033
Hashemi, E., Ariza, J., Rogers, H., Noctor, S. C. & Martinez-Cerdeno, V. The number of parvalbumin-expressing interneurons is decreased in the prefrontal cortex in autism. Cereb. Cortex 27, 1931–1943 (2017).
pubmed: 26922658
Thomson, J. A. et al. Embryonic stem cell lines derived from human blastocysts. Science 282, 1145–1147 (1998).
pubmed: 9804556 doi: 10.1126/science.282.5391.1145
Tchieu, J. et al. Female human iPSCs retain an inactive X chromosome. Cell Stem Cell 7, 329–342 (2010).
pubmed: 20727844 pmcid: 2935700 doi: 10.1016/j.stem.2010.06.024
Rousso, D. L., Gaber, Z. B., Wellik, D., Morrisey, E. E. & Novitch, B. G. Coordinated actions of the forkhead protein Foxp1 and Hox proteins in the columnar organization of spinal motor neurons. Neuron 59, 226–240 (2008).
pubmed: 18667151 pmcid: 2547125 doi: 10.1016/j.neuron.2008.06.025
Lee, B. et al. Dlx1/2 and Otp coordinate the production of hypothalamic GHRH- and AgRP-neurons. Nat. Commun. 9, 2026 (2018).
pubmed: 29795232 pmcid: 5966420 doi: 10.1038/s41467-018-04377-4
Kuwajima, T., Nishimura, I. & Yoshikawa, K. Necdin promotes GABAergic neuron differentiation in cooperation with Dlx homeodomain proteins. J. Neurosci. 26, 5383–5392 (2006).
pubmed: 16707790 pmcid: 6675313 doi: 10.1523/JNEUROSCI.1262-06.2006
Schindelin, J. et al. Fiji: an open-source platform for biological-image analysis. Nat. Methods 9, 676–682 (2012).
doi: 10.1038/nmeth.2019 pubmed: 22743772
Butler, A., Hoffman, P., Smibert, P., Papalexi, E. & Satija, R. Integrating single-cell transcriptomic data across different conditions, technologies, and species. Nat. Biotechnol. 36, 411–420 (2018).
pubmed: 29608179 pmcid: 6700744 doi: 10.1038/nbt.4096
Stuart, T. et al. Comprehensive integration of single-cell data. Cell 177, 1888–1902 (2019).
pubmed: 31178118 pmcid: 6687398 doi: 10.1016/j.cell.2019.05.031
Welch, J. D. et al. Single-cell multi-omic integration compares and contrasts features of brain cell identity. Cell 177, 1873–1887 (2019).
pubmed: 31178122 pmcid: 6716797 doi: 10.1016/j.cell.2019.05.006
Yuste, R. et al. A community-based transcriptomics classification and nomenclature of neocortical cell types. Nat. Neurosci. 23, 1456–1468 (2020).
pubmed: 32839617 pmcid: 7683348 doi: 10.1038/s41593-020-0685-8
Krienen, F. M. et al. Innovations present in the primate interneuron repertoire. Nature 586, 262–269 (2020).
pubmed: 32999462 pmcid: 7957574 doi: 10.1038/s41586-020-2781-z
Mayer, C. et al. Developmental diversification of cortical inhibitory interneurons. Nature 555, 457–462 (2018).
pubmed: 29513653 pmcid: 6052457 doi: 10.1038/nature25999
Hodge, R. D. et al. Conserved cell types with divergent features in human versus mouse cortex. Nature 573, 61–68 (2019).
pubmed: 31435019 pmcid: 6919571 doi: 10.1038/s41586-019-1506-7
Gouwens, N. W. et al. Integrated morphoelectric and transcriptomic classification of cortical GABAergic. Cell 183, 935–953 (2020).
pubmed: 33186530 doi: 10.1016/j.cell.2020.09.057 pmcid: 7781065
Polioudakis, D. et al. A single-cell transcriptomic atlas of human neocortical development during mid-gestation. Neuron 103, 785–801 (2019).
pubmed: 31303374 pmcid: 6831089 doi: 10.1016/j.neuron.2019.06.011
Cao, Y. et al. scDC: single-cell differential composition analysis. BMC Bioinformatics 20, 721 (2019).
pubmed: 31870280 pmcid: 6929335 doi: 10.1186/s12859-019-3211-9
Raudvere, U. et al. g:Profiler: a web server for functional enrichment analysis and conversions of gene lists. Nucleic Acids Res. 47, W191–W198 (2019).
pubmed: 31066453 pmcid: 6602461 doi: 10.1093/nar/gkz369
Reimand, J., Kull, M., Peterson, H., Hansen, J. & Vilo, J. g:Profiler—a web-based toolset for functional profiling of gene lists from large-scale experiments. Nucleic Acids Res. 35, W193–W200 (2007).
pubmed: 17478515 pmcid: 1933153 doi: 10.1093/nar/gkm226
Chen, T. W. et al. Ultrasensitive fluorescent proteins for imaging neuronal activity. Nature 499, 295–300 (2013).
pubmed: 23868258 pmcid: 3777791 doi: 10.1038/nature12354

Auteurs

Ranmal A Samarasinghe (RA)

Department of Neurobiology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA, USA.
Intellectual Development and Disabilities Research Center, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.

Osvaldo A Miranda (OA)

Department of Neurobiology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA, USA.
Intellectual Development and Disabilities Research Center, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
ORCID: 0000-0001-6618-6889

Jessie E Buth (JE)

Department of Neurobiology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA, USA.
Intellectual Development and Disabilities Research Center, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.

Simon Mitchell (S)

Institute for Quantitative and Computational Biosciences, Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA, USA.
Brighton and Sussex Medical School, Falmer, United Kingdom.

Isabella Ferando (I)

Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.

Momoko Watanabe (M)

Department of Neurobiology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA, USA.
Intellectual Development and Disabilities Research Center, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
Department of Anatomy & Neurobiology, Sue & Bill Gross Stem Cell Research Center, School of Medicine, University of California, Irvine, Irvine, CA, USA.
ORCID: 0000-0001-5014-2849

Thomas F Allison (TF)

Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA, USA.
Department of Biological Chemistry, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.

Arinnae Kurdian (A)

Department of Neurobiology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA, USA.
Intellectual Development and Disabilities Research Center, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
CIRM CSUN-UCLA Stem Cell Training Program, California State University, Northridge, CA, USA.

Namie N Fotion (NN)

Department of Neurobiology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA, USA.
Intellectual Development and Disabilities Research Center, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
ORCID: 0000-0001-8022-8651

Michael J Gandal (MJ)

Intellectual Development and Disabilities Research Center, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
ORCID: 0000-0001-5800-5128

Peyman Golshani (P)

Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
Intellectual Development and Disabilities Research Center, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, Los Angeles, CA, USA.
West Los Angeles VA Medical Center, Los Angeles, CA, USA.
ORCID: 0000-0002-5406-7695

Kathrin Plath (K)

Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA, USA.
Department of Biological Chemistry, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
ORCID: 0000-0001-7796-3372

William E Lowry (WE)

Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA, USA.
Department of Molecular, Cell, and Developmental Biology, University of California, Los Angeles, Los Angeles, CA, USA.
ORCID: 0000-0003-2932-2276

Jack M Parent (JM)

Department of Neurology, University of Michigan Medical School, Ann Arbor, MI, USA.
Michigan Neuroscience Institute, University of Michigan, Ann Arbor, MI, USA.
Ann Arbor VA Healthcare System, University of Michigan Medical School, Ann Arbor, MI, USA.
ORCID: 0000-0002-2972-1528

Istvan Mody (I)

Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
Department of Physiology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.

Bennett G Novitch (BG)

Department of Neurobiology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA. bnovitch@ucla.edu.
Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA, USA. bnovitch@ucla.edu.
Intellectual Development and Disabilities Research Center, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA. bnovitch@ucla.edu.
ORCID: 0000-0002-2696-3708

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Classifications MeSH

questionsmedicales.fr › Personnes › Tranches d'âge › Adulte › Identification of neural oscillations and...
questionsmedicales.fr › Composés hétérocycliques › Composés hétérocycliques à cycles fusionnés › Composés hétérobicycliques › Benzothiazoles › Identification of neural oscillations and...
questionsmedicales.fr › Système nerveux › Système nerveux central › Encéphale › Identification of neural oscillations and...
questionsmedicales.fr › Phénomènes physiologiques cellulaires › Transduction du signal › Systèmes de seconds messagers › Signalisation calcique › Identification of neural oscillations and...
questionsmedicales.fr › Personnes › Tranches d'âge › Enfant › Enfant d'âge préscolaire › Identification of neural oscillations and...
questionsmedicales.fr › Maladies du système nerveux › Maladies du système nerveux central › Encéphalopathies › Épilepsie › Identification of neural oscillations and...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Identification of neural oscillations and...
questionsmedicales.fr › Cellules › Cellules souches › Cellules souches pluripotentes › Cellules souches pluripotentes induites › Identification of neural oscillations and...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Nucléoprotéines › Protéines chromosomiques nonhistones › Protéine-2 de liaison au CpG méthylé › Identification of neural oscillations and...
questionsmedicales.fr › Système nerveux › Réseau nerveux › Identification of neural oscillations and...
questionsmedicales.fr › Phénomènes physiologiques de l'appareil locomoteur et du système nerveux › Phénomènes physiologiques du système nerveux › Neurogenèse › Identification of neural oscillations and...
questionsmedicales.fr › Techniques d'investigation › Neuroimagerie › Identification of neural oscillations and...
questionsmedicales.fr › Cellules › Neurones › Identification of neural oscillations and...
questionsmedicales.fr › Malformations et maladies congénitales, héréditaires et néonatales › Maladies génétiques congénitales › Maladies neurodégénératives héréditaires › Retard mental lié à l'X › Syndrome de Rett › Identification of neural oscillations and...
questionsmedicales.fr › Techniques d'investigation › Techniques cytologiques › Analyse sur cellule unique › Identification of neural oscillations and...
questionsmedicales.fr › Cellules › Structures cellulaires › Membrane cellulaire › Structures de la membrane cellulaire › Jonctions intercellulaires › Synapses › Identification of neural oscillations and...
questionsmedicales.fr › Composés chimiques organiques › Hydrocarbures › Hydrocarbures cycliques › Hydrocarbures aromatiques › Dérivés du benzène › Toluène › Identification of neural oscillations and...
questionsmedicales.fr › Phénomènes génétiques › Structures génétiques › Transcriptome › Identification of neural oscillations and...