Xenotransplanted Human Cortical Neurons Reveal Species-Specific Development and Functional Integration into Mouse Visual Circuits

Overview

Journal Neuron

Publisher Cell Press

Specialty Neurology

Date 2019 Nov 26

PMID 31761708

Citations 84

Authors

Daniele Linaro

Ben Vermaercke

Ryohei Iwata

Arjun Ramaswamy

Baptiste Libe-Philippot

Leila Boubakar

Brittany A Davis

Keimpe Wierda

Kristofer Davie

Suresh Poovathingal

Pier-Andree Penttila

Angeline Bilheu

Lore De Bruyne

David Gall

Karl-Klaus Conzelmann

Vincent Bonin

Pierre Vanderhaeghen

Affiliations

Soon will be listed here.

Abstract

How neural circuits develop in the human brain has remained almost impossible to study at the neuronal level. Here, we investigate human cortical neuron development, plasticity, and function using a mouse/human chimera model in which xenotransplanted human cortical pyramidal neurons integrate as single cells into the mouse cortex. Combined neuronal tracing, electrophysiology, and in vivo structural and functional imaging of the transplanted cells reveal a coordinated developmental roadmap recapitulating key milestones of human cortical neuron development. The human neurons display a prolonged developmental timeline, indicating the neuron-intrinsic retention of juvenile properties as an important component of human brain neoteny. Following maturation, human neurons in the visual cortex display tuned, decorrelated responses to visual stimuli, like mouse neurons, demonstrating their capacity for physiological synaptic integration in host cortical circuits. These findings provide new insights into human neuronal development and open novel avenues for the study of human neuronal function and disease. VIDEO ABSTRACT.

Citing Articles

Long-Term Engraftment of Cryopreserved Human Neurons for In Vivo Disease Modeling in Neurodegenerative Disease.

Marmion D, Deng P, Hiller B, Lewis R, Harms L, Cameron D Biology (Basel). 2025; 14(2).

PMID: 40001985 PMC: 11852092. DOI: 10.3390/biology14020217.

Using cortical organoids to understand the pathogenesis of malformations of cortical development.

Winden K, Gisser I, Sahin M Front Neurosci. 2025; 18:1522652.

PMID: 39881808 PMC: 11774837. DOI: 10.3389/fnins.2024.1522652.

Transplanted deep-layer cortical neuroblasts integrate into host neural circuits and alleviate motor defects in hypoxic-ischemic encephalopathy injured mice.

Wu M, Xu Y, Ji X, Zhou Y, Li Y, Feng B Stem Cell Res Ther. 2024; 15(1):422.

PMID: 39533375 PMC: 11558921. DOI: 10.1186/s13287-024-04049-9.

Unraveling mechanisms of human brain evolution.

Lancaster M Cell. 2024; 187(21):5838-5857.

PMID: 39423803 PMC: 7617105. DOI: 10.1016/j.cell.2024.08.052.

Synaptic neoteny of human cortical neurons requires species-specific balancing of SRGAP2-SYNGAP1 cross-inhibition.

Libe-Philippot B, Iwata R, Recupero A, Wierda K, Bernal Garcia S, Hammond L Neuron. 2024; 112(21):3602-3617.e9.

PMID: 39406239 PMC: 11546603. DOI: 10.1016/j.neuron.2024.08.021.

References

Bufill E, Agusti J, Blesa R . Human neoteny revisited: The case of synaptic plasticity. Am J Hum Biol. 2011; 23(6):729-39. DOI: 10.1002/ajhb.21225. View

Mrzljak L, Uylings H, Van Eden C, Judas M . Neuronal development in human prefrontal cortex in prenatal and postnatal stages. Prog Brain Res. 1990; 85:185-222. DOI: 10.1016/s0079-6123(08)62681-3. View

Cruz-Martin A, Crespo M, Portera-Cailliau C . Delayed stabilization of dendritic spines in fragile X mice. J Neurosci. 2010; 30(23):7793-803. PMC: 2903441. DOI: 10.1523/JNEUROSCI.0577-10.2010. View

Anderson S, Vanderhaeghen P . Cortical neurogenesis from pluripotent stem cells: complexity emerging from simplicity. Curr Opin Neurobiol. 2014; 27:151-7. PMC: 4386058. DOI: 10.1016/j.conb.2014.03.012. View

Nicholas C, Chen J, Tang Y, Southwell D, Chalmers N, Vogt D . Functional maturation of hPSC-derived forebrain interneurons requires an extended timeline and mimics human neural development. Cell Stem Cell. 2013; 12(5):573-86. PMC: 3699205. DOI: 10.1016/j.stem.2013.04.005. View

Suzuki I, Vanderhaeghen P . Is this a brain which I see before me? Modeling human neural development with pluripotent stem cells. Development. 2015; 142(18):3138-50. DOI: 10.1242/dev.120568. View

Pfeiffer B, Zang T, Wilkerson J, Taniguchi M, Maksimova M, Smith L . Fragile X mental retardation protein is required for synapse elimination by the activity-dependent transcription factor MEF2. Neuron. 2010; 66(2):191-7. PMC: 2864778. DOI: 10.1016/j.neuron.2010.03.017. View

Rakic P, Bourgeois J, Eckenhoff M, Zecevic N, Goldman-Rakic P . Concurrent overproduction of synapses in diverse regions of the primate cerebral cortex. Science. 1986; 232(4747):232-5. DOI: 10.1126/science.3952506. View

Jiang X, Shen S, Cadwell C, Berens P, Sinz F, Ecker A . Principles of connectivity among morphologically defined cell types in adult neocortex. Science. 2015; 350(6264):aac9462. PMC: 4809866. DOI: 10.1126/science.aac9462. View

10.

Mizuno H, Ikezoe K, Nakazawa S, Sato T, Kitamura K, Iwasato T . Patchwork-Type Spontaneous Activity in Neonatal Barrel Cortex Layer 4 Transmitted via Thalamocortical Projections. Cell Rep. 2018; 22(1):123-135. DOI: 10.1016/j.celrep.2017.12.012. View

11.

Beaulieu-Laroche L, Toloza E, van der Goes M, Lafourcade M, Barnagian D, Williams Z . Enhanced Dendritic Compartmentalization in Human Cortical Neurons. Cell. 2018; 175(3):643-651.e14. PMC: 6197488. DOI: 10.1016/j.cell.2018.08.045. View

12.

Trujillo C, Gao R, Negraes P, Gu J, Buchanan J, Preissl S . Complex Oscillatory Waves Emerging from Cortical Organoids Model Early Human Brain Network Development. Cell Stem Cell. 2019; 25(4):558-569.e7. PMC: 6778040. DOI: 10.1016/j.stem.2019.08.002. View

13.

Astick M, Vanderhaeghen P . From Human Pluripotent Stem Cells to Cortical Circuits. Curr Top Dev Biol. 2018; 129:67-98. DOI: 10.1016/bs.ctdb.2018.02.011. View

14.

HUTTENLOCHER P, De Courten C, Garey L, Van Der Loos H . Synaptic development in human cerebral cortex. Int J Neurol. 1982; 16-17:144-54. View

15.

Nevian T, Sakmann B . Spine Ca2+ signaling in spike-timing-dependent plasticity. J Neurosci. 2006; 26(43):11001-13. PMC: 6674669. DOI: 10.1523/JNEUROSCI.1749-06.2006. View

16.

Ting J, Daigle T, Chen Q, Feng G . Acute brain slice methods for adult and aging animals: application of targeted patch clamp analysis and optogenetics. Methods Mol Biol. 2014; 1183:221-42. PMC: 4219416. DOI: 10.1007/978-1-4939-1096-0_14. View

17.

Zuo Y, Lin A, Chang P, Gan W . Development of long-term dendritic spine stability in diverse regions of cerebral cortex. Neuron. 2005; 46(2):181-9. DOI: 10.1016/j.neuron.2005.04.001. View

18.

Di Lullo E, Kriegstein A . The use of brain organoids to investigate neural development and disease. Nat Rev Neurosci. 2017; 18(10):573-584. PMC: 5667942. DOI: 10.1038/nrn.2017.107. View

19.

Liu X, Somel M, Tang L, Yan Z, Jiang X, Guo S . Extension of cortical synaptic development distinguishes humans from chimpanzees and macaques. Genome Res. 2012; 22(4):611-22. PMC: 3317144. DOI: 10.1101/gr.127324.111. View

20.

Takashima S, Becker L, Armstrong D, Chan F . Abnormal neuronal development in the visual cortex of the human fetus and infant with down's syndrome. A quantitative and qualitative Golgi study. Brain Res. 1981; 225(1):1-21. DOI: 10.1016/0006-8993(81)90314-0. View