02018nas a2200301   4500000000100000000000100001008004100002260001500043653001800058653002500076100002200101700001300123700001800136700001600154700001800170700001700188700001700205700001900222700001500241700001700256700001700273245013800290856005500428300000900483490000700492520120300499022001401702       2023                            d  c2023-06-2410aSchizophrenia10aSynaptic development1 aRebecca Sebastian1 aKang Jin1 aNarciso Pavon1 aRuby Bansal1 aAndrew Potter1 aYoonjae Song1 aJuliana Babu1 aRafael Gabriel1 aYubing Sun1 aBruce Aronow1 aChangHui Pak00aSchizophrenia-associated NRXN1 deletions induce developmental-timing- and cell-type-specific vulnerabilities in human brain organoids  uhttps://www.nature.com/articles/s41467-023-39420-6  a37700 v143 aDe 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.  a2041-1723