ChangHui Pak

Understanding how synapses develop and undergo plasticity during normal brain development and how they go awry during disease states. Using unique cellular tools derived from human iPSCs including human induced neuronal cells and 3D brain organoids, we aim to discover how synaptic dysfunction predisposes individuals with specific neuropsychiatric conditions.

PhD: Emory University School of Medicine

Postdoc: Stanford University School of Medicine

The overarching scientific interest of the Pak lab is to understand the molecular and cellular basis of how our brains develop and function from early embryonic stages through adulthood and to investigate how disruptions in these pathways contribute to neurodevelopmental/neuropsychiatric disorders. Specifically, we are interested in pursuing this big task by focusing on synapse development, a developmental period when neurons (and astrocytes) make active connections with one another. Synapses are polarized cellular junctions that organize fast and efficient signaling and communication between nerve cells. We now know from multiple human genetic studies that brain disorders (both neurodevelopmental and neurodegenerative disorders) arise from synaptic dysfunction.

To achieve this mission, we not only have to figure out the underlying biology of synapse formation, specification, and maintenance in healthy and disease states, but we must also develop novel cellular and molecular tools to approach these questions from human cellular contexts. In our lab, we utilize human pluripotent stem cell-derived neural models (i.e. induced neurons and brain organoids) to probe human synaptic biology and disease mechanisms.

Currently, in the lab, we are focusing on three major research areas:

• Signaling mechanisms in neurodevelopment
• Functional analysis of pathogenic variants in neuropsychiatric disorders
• Development of improved human iPSC-based tools

We use a combination of approaches from gene editing, patient-derived iPSCs, biochemistry, omics, and electrophysiology and collaborate with experts in biochemistry, neurobiology, human genetics, and engineering to approach these questions from diverse scientific perspectives.

Pak Lab Website

* denotes corresponding authorship, † denotes trainees in the lab

• Pavon N†, Diep K†, Yang F, Sebastian R†, Martinez-Martin B†, Ranjan R, Sun Y*, Pak C*. “Patterning ganglionic eminences in developing human brain organoids using morphogen induced gradient device.” Cell Reports Methods. 2024 Jan 22;4(1):100689.doi: 10.1016/j.crmeth.2023.100689. PMID: 38228151
• Sebastian R†, Jin K, Pavon N†, Bansal R†, Potter A, Song Y†, Babu J†, Gabriel R†, Sun Y, Aronow B, Pak C*. “Schizophrenia-associated NRXN1 deletions induce developmental-timing- and cell-type-specific vulnerabilities in human brain organoids.” Nature Communications. 2023 Jun 24;14(1):3770. doi: 10.1038/s41467-023-39420-6. PMID: 37355690
• Dawes P, Smullen M, Fernandez-Fontaine A, Zhang Y, English J†, Uddin M, Pak C, Church GM, Chan Y, Lim ET. "oFlowSeq: A multiplexed quantitative approach to identify genes affecting cell type enrichment using mosaic CRISPR-Cas9 edited cerebral organoids." Human Genetics. 2023 In press. PMID: 36877372
• English J†, McSweeney D†, Howell E†, Ribbe F†, Pak C*. “Generation of mixed cortical glutamatergic and GABAergic induced neurons.” Methods in Molecular Biology. Book: Stem Cell-Based Neural Model Systems for Brain Disorders. 2023 In press. DOI: 10.1007/978-1-0716-3287-1_3. PMID: 37300764
• Sebastian R†, Pavon N†, Diep K†, Song Y†, Pak C*. “Method to generate patterned forebrain organoids from iPSCs.” Methods in Molecular Biology. Book: Stem Cell-Based Neural Model Systems for Brain Disorders. 2023 In press. DOI: 10.1007/978-1-0716-3287-1_13. PMID: 37300774
• McSweeney D†, English J†, Howell E†, Ribbe F†, Pak C*. “Measuring neuronal network activity using induced neuronal cells.” Methods in Molecular Biology. Book: Stem Cell-Based Neural Model Systems for Brain Disorders. 2023 In press. DOI: 10.1007/978-1-0716-3287-1_19. PMID: 37300780
• Wang L, Mirabella VR, Dai R, Su X, Xu R, Jadali A, Bernabucci M, Singh I, Chen Y, Tian Y, Jiang P, Kwan KY, Pak C, Liu C, Comoletti D, Hart RP, Chen C, Sudhof TC, Pang ZP. “Analyses of the autism-associated Neuroligin-3 R451C mutation in human neurons reveals a gain-of-function synaptic mechanism.” Molecular Psychiatry. 2022 Oct 24. doi: 10.1038/s41380-022-01834-x. Online ahead of print. PMID: 36280753
• McSweeney D†, Gabriel R†, Jin K, Pang ZP, Aronow B, Pak C*. “CASK loss-of-function differentially regulates neuronal maturation and synaptic function in human induced cortical excitatory neurons." iScience 2022 Sep 23;25(10):105187. PMID: 36262316.
• Sebastian R†, Song Y†, Pak C*. “Probing the molecular and cellular pathological mechanisms of schizophrenia using human induced pluripotent stem cell models.” Schizophrenia Research. 2022 Jul 11;S0920-9964(22)00263-8. PMID: 35835709
• Pak C*, Sun Y*. “Organoids: expanding applications enabled by emerging technologies.” Editorial Review. Special issue on “Organoids,” Journal of Molecular Biology. 2021 Dec 20;167411. Online ahead of print. PMID: 34933020
• Pak C*, Danko T, Mirabella V, Wang J, Liu Y, Vangipuram M, Grieder S, Zhang X, Ward T, Huang A, Jin K, Dexheimer P, Bardes E, Mittelpunkt A, Ma J, McLachlan M, Moore JC, Qu P, Purmann C, Dage JL, Swanson BJ, Urban AE, Aronow BJ, Pang ZP, Levinson DF, Wernig M, Südhof TC*. “Cross-platform validation of neurotransmitter release impairments in schizophrenia patient-derived NRXN1-mutant neurons.” PNAS 2021, Jun 1;118(22):e2025598118. PMID: 34035170 *co-corresponding author.
• Fuccillo MV*, Pak C*. “Copy number variants in neurexin genes: phenotypes and mechanisms.” Current Opinion in Genetics and Development. 2021 Mar20:68:64-70. PMID: 33756113
• Li N, Yang F, Parthasarathy S, St. Pierre S, Hong K, Pavon N†, Pak C, Sun Y. “Patterning Neuroepithelial Cell Sheet via a Sustained Chemical Gradient Generated by Localized Passive Diffusion Devices.” ACS Biomaterial Science Engineering. 2021, Apr 12;7(4):1713-1721. PMID: 33751893
• Xie T, Kang J, Pak C, Yuan H, Sun Y. “Temporal modulations of NODAL, BMP and WNT signals guide the spatial patterning in self-organized human ectoderm tissues.” Matter 2020, 2(6) June:1621-1638. “PMC Journal in process”
• Galarza S, Crosby AJ, Pak C, Peyton SR. “Control of Astrocyte Quiescence and Activation in a Synthetic Brain Hydrogel.” Advanced Healthcare Materials 2020, 9(4):31901419 PMID: 31943839