ChangHui Pak

Understanding synapses in the human brain.

PhD: Emory University School of Medicine

Postdoc: Stanford University School of Medicine

The Pak Lab is broadly interested in understanding how the human brain develops and functions from early embryonic stages through adulthood, and how disruptions in these processes contribute to neurodevelopmental and neuropsychiatric disorders. We focus on synapse development—a critical period when neurons and astrocytes form active, polarized connections that enable fast and efficient communication across neural circuits. Extensive human genetic studies have shown that synaptic dysfunction is a core feature of both neurodevelopmental and neurodegenerative brain disorders.

To address these questions, we aim not only to uncover the fundamental biology of synapse formation, specification, and maintenance in health and disease, but also to advance new cellular and molecular tools that allow us to investigate these processes in human-relevant systems. Our lab utilizes human pluripotent stem cell-derived neural models—including induced neurons (iNs) and brain organoids—to study human synaptic biology and disease mechanisms.

Our current projects center on three major research areas:

• Synaptic dysfunction in complex brain disorders
• Developmental deficits associated with neurodevelopmental syndromes
• Development of improved human iPSC-based tools

We take an integrative approach combining CRISPR/Cas9 gene editing, patient-derived iPSCs, biochemistry, single-cell transcriptomics, proteomics, and electrophysiology. Our work is enriched through collaborations with experts in neurobiology, human genetics, biochemistry, and engineering, as well as with physicians who care for individuals with neurodevelopmental disorders.

* denotes corresponding authorship, † denotes trainees in the lab

• Pavon N†, Sun Y, Pak C*. “Cell Type Specification and Diversity in Subpallial Organoids.” Frontiers in Genetics. 2024 Sep 26;15:1440583. doi: 10.3389/fgene.2024.1440583. PMID: 39391063
• 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