Synaptic Plasticity in Human Thalamocortical Assembloids

Overview

Journal bioRxiv

Date 2024 Feb 14

PMID 38352415

Authors

Mary H Patton

Kristen T Thomas

Ildar T Bayazitov

Kyle D Newman

Nathaniel B Kurtz

Camenzind G Robinson

Cody A Ramirez

Alexandra J Trevisan

Jay B Bikoff

Samuel T Peters

Shondra M Pruett-Miller

Yanbo Jiang

Andrew B Schild

Anjana Nityanandam

Stanislav S Zakharenko

Affiliations

Soon will be listed here.

Abstract

Synaptic plasticities, such as long-term potentiation (LTP) and depression (LTD), tune synaptic efficacy and are essential for learning and memory. Current studies of synaptic plasticity in humans are limited by a lack of adequate human models. Here, we modeled the thalamocortical system by fusing human induced pluripotent stem cell-derived thalamic and cortical organoids. Single-nucleus RNA-sequencing revealed that most cells in mature thalamic organoids were glutamatergic neurons. When fused to form thalamocortical assembloids, thalamic and cortical organoids formed reciprocal long-range axonal projections and reciprocal synapses detectable by light and electron microscopy, respectively. Using whole-cell patch-clamp electrophysiology and two-photon imaging, we characterized glutamatergic synaptic transmission. Thalamocortical and corticothalamic synapses displayed short-term plasticity analogous to that in animal models. LTP and LTD were reliably induced at both synapses; however, their mechanisms differed from those previously described in rodents. Thus, thalamocortical assembloids provide a model system for exploring synaptic plasticity in human circuits.

References

Bagley J, Reumann D, Bian S, Levi-Strauss J, Knoblich J . Fused cerebral organoids model interactions between brain regions. Nat Methods. 2017; 14(7):743-751. PMC: 5540177. DOI: 10.1038/nmeth.4304. View

Chun S, Bayazitov I, Blundon J, Zakharenko S . Thalamocortical long-term potentiation becomes gated after the early critical period in the auditory cortex. J Neurosci. 2013; 33(17):7345-57. PMC: 3679664. DOI: 10.1523/JNEUROSCI.4500-12.2013. View

Hensch T . Critical period regulation. Annu Rev Neurosci. 2004; 27:549-79. DOI: 10.1146/annurev.neuro.27.070203.144327. View

Anton-Bolanos N, Sempere-Ferrandez A, Guillamon-Vivancos T, Martini F, Perez-Saiz L, Gezelius H . Prenatal activity from thalamic neurons governs the emergence of functional cortical maps in mice. Science. 2019; 364(6444):987-990. PMC: 7611000. DOI: 10.1126/science.aav7617. View

Kanton S, Boyle M, He Z, Santel M, Weigert A, Sanchis-Calleja F . Organoid single-cell genomic atlas uncovers human-specific features of brain development. Nature. 2019; 574(7778):418-422. DOI: 10.1038/s41586-019-1654-9. View

Beierlein M, Fall C, Rinzel J, Yuste R . Thalamocortical bursts trigger recurrent activity in neocortical networks: layer 4 as a frequency-dependent gate. J Neurosci. 2002; 22(22):9885-94. PMC: 6757840. View

Stratford K, Martin K, Bannister N, Jack J . Excitatory synaptic inputs to spiny stellate cells in cat visual cortex. Nature. 1996; 382(6588):258-61. DOI: 10.1038/382258a0. View

Beierlein M, Connors B . Short-term dynamics of thalamocortical and intracortical synapses onto layer 6 neurons in neocortex. J Neurophysiol. 2002; 88(4):1924-32. DOI: 10.1152/jn.2002.88.4.1924. View

Agoglia R, Sun D, Birey F, Yoon S, Miura Y, Sabatini K . Primate cell fusion disentangles gene regulatory divergence in neurodevelopment. Nature. 2021; 592(7854):421-427. PMC: 8719633. DOI: 10.1038/s41586-021-03343-3. View

10.

Pasca A, Sloan S, Clarke L, Tian Y, Makinson C, Huber N . Functional cortical neurons and astrocytes from human pluripotent stem cells in 3D culture. Nat Methods. 2015; 12(7):671-8. PMC: 4489980. DOI: 10.1038/nmeth.3415. View

11.

Rose H, Metherate R . Auditory thalamocortical transmission is reliable and temporally precise. J Neurophysiol. 2005; 94(3):2019-30. DOI: 10.1152/jn.00860.2004. View

12.

Feldman D, Nicoll R, Malenka R, Isaac J . Long-term depression at thalamocortical synapses in developing rat somatosensory cortex. Neuron. 1998; 21(2):347-57. DOI: 10.1016/s0896-6273(00)80544-9. View

13.

Li Y, Muffat J, Omer A, Bosch I, Lancaster M, Sur M . Induction of Expansion and Folding in Human Cerebral Organoids. Cell Stem Cell. 2017; 20(3):385-396.e3. PMC: 6461394. DOI: 10.1016/j.stem.2016.11.017. View

14.

Keaveney M, Tseng H, Ta T, Gritton H, Man H, Han X . A MicroRNA-Based Gene-Targeting Tool for Virally Labeling Interneurons in the Rodent Cortex. Cell Rep. 2018; 24(2):294-303. PMC: 6095194. DOI: 10.1016/j.celrep.2018.06.049. View

15.

Viswanathan S, Sheikh A, Looger L, Kanold P . Molecularly Defined Subplate Neurons Project Both to Thalamocortical Recipient Layers and Thalamus. Cereb Cortex. 2016; 27(10):4759-4768. PMC: 6059176. DOI: 10.1093/cercor/bhw271. View

16.

Kim J, Miura Y, Li M, Revah O, Selvaraj S, Birey F . Human assembloids reveal the consequences of CACNA1G gene variants in the thalamocortical pathway. Neuron. 2024; 112(24):4048-4059.e7. DOI: 10.1016/j.neuron.2024.09.020. View

17.

Crair M, Malenka R . A critical period for long-term potentiation at thalamocortical synapses. Nature. 1995; 375(6529):325-8. DOI: 10.1038/375325a0. View

18.

Saleem A, Santos A, Aquilino M, Sivitilli A, Attisano L, Carlen P . Modelling hyperexcitability in human cerebral cortical organoids: Oxygen/glucose deprivation most effective stimulant. Heliyon. 2023; 9(4):e14999. PMC: 10113787. DOI: 10.1016/j.heliyon.2023.e14999. View

19.

Szegedi V, Paizs M, Csakvari E, Molnar G, Barzo P, Tamas G . Plasticity in Single Axon Glutamatergic Connection to GABAergic Interneurons Regulates Complex Events in the Human Neocortex. PLoS Biol. 2016; 14(11):e2000237. PMC: 5102409. DOI: 10.1371/journal.pbio.2000237. View

20.

Cadwell C, Palasantza A, Jiang X, Berens P, Deng Q, Yilmaz M . Electrophysiological, transcriptomic and morphologic profiling of single neurons using Patch-seq. Nat Biotechnol. 2015; 34(2):199-203. PMC: 4840019. DOI: 10.1038/nbt.3445. View