Investigating synaptic mechanisms underlying autism spectrum disorders and schizophrenia
Advances in human genome sequencing have revealed that complex brain disorders such as autism spectrum disorders (ASD) and schizophrenia (SCZ) are shaped by both rare and common genetic variants. Notably, these risk variants are strongly enriched in genes regulating synaptic function, converging on pathways involved in synapse assembly, synaptic transmission, and synaptic homeostasis.
A key genetic locus implicated in both ASD and SCZ is 2p16.3/NRXN1, where copy number deletions disrupt a presynaptic cell adhesion molecule essential for specifying and maintaining synaptic properties. In the Pak Lab, we use NRXN1 as a genetic anchor to investigate how synaptic biology is altered in these disorders, aiming to uncover disorder-relevant mechanisms with translational significance.
As a stem cell laboratory, we leverage these genetic insights through the use of human induced pluripotent stem cells (iPSCs), allowing us to model human genetic variation and its functional consequences in neurodevelopment and synaptic biology. We employ CRISPR/Cas9 genome editing to introduce disease-relevant mutations into control iPSC lines, and we generate donor-derived iPSCs from individuals with neuropsychiatric disorders alongside matched controls. These iPSC models are differentiated into specific neural cell types in both 2D cultures and 3D brain organoids, enabling us to study developmental trajectories, cellular biology, gene expression programs, and functional synaptic connectivity in a human-relevant context.
See publications related to this research focus:
Pak et al., 2015 Cell Stem Cell
Fuccillo and Pak 2021 Current Opinions in Genetics and Development
Sebastian et al., 2023 Nature Communications
English et al., 2025 biorxiv – link