@article{2121,
  keywords = {Schizophrenia, Synaptic development},
  author = {Rebecca Sebastian and Kang Jin and Narciso Pavon and Ruby Bansal and Andrew Potter and Yoonjae Song and Juliana Babu and Rafael Gabriel and Yubing Sun and Bruce Aronow and ChangHui Pak},
  title = {Schizophrenia-associated NRXN1 deletions induce developmental-timing- and cell-type-specific vulnerabilities in human brain organoids},
  abstract = {De novo mutations and copy number deletions in NRXN1 (2p16.3) pose a significant risk for schizophrenia (SCZ). It is unclear how NRXN1 deletions impact cortical development in a cell type-specific manner and disease background modulates these phenotypes. Here, we leveraged human pluripotent stem cell-derived forebrain organoid models carrying NRXN1 heterozygous deletions in isogenic and SCZ patient genetic backgrounds and conducted single-cell transcriptomic analysis over the course of brain organoid development from 3 weeks to 3.5 months. Intriguingly, while both deletions similarly impacted molecular pathways associated with ubiquitin-proteasome system, alternative splicing, and synaptic signaling in maturing glutamatergic and GABAergic neurons, SCZ-NRXN1 deletions specifically perturbed developmental trajectories of early neural progenitors and accumulated disease-specific transcriptomic signatures. Using calcium imaging, we found that both deletions led to long-lasting changes in spontaneous and synchronous neuronal networks, implicating synaptic dysfunction. Our study reveals developmental-timing- and cell-type-dependent actions of NRXN1 deletions in unique genetic contexts.},
  year = {2023},
  journal = {Nature Communications},
  volume = {14},
  pages = {3770},
  month = {2023-06-24},
  issn = {2041-1723},
  url = {https://www.nature.com/articles/s41467-023-39420-6},
  doi = {10.1038/s41467-023-39420-6},
  language = {en},
}