Sudhof, T. C. Synaptic neurexin complexes: a molecular code for the logic of neural circuits. Cell 171, 745–769 (2017).
De Wit, J. & Ghosh, A. Specification of synaptic connectivity by cell surface interactions. Nat. Rev. Neurosci. 17, 22–35 (2016).
Gomez, A. M., Traunmüller, L. & Scheiffele, P. Neurexins: molecular codes for shaping neuronal synapses. Nat. Rev. Neurosci. 22, 137–151 (2021).
Schreiner, D. et al. Targeted combinatorial alternative splicing generates brain region-specific repertoires of neurexins. Neuron 84, 386–398 (2014).
Fuccillo, M. V. et al. Single-cell mRNA profiling reveals cell-type-specific expression of neurexin isoforms. Neuron 87, 326–340 (2015).
Marshall, C. R. et al. Contribution of copy number variants to schizophrenia from a genome-wide study of 41,321 subjects. Nat. Genet. 49, 27–35 (2017).
Matsunami, N. et al. Identification of rare recurrent copy number variants in high-risk autism families and their prevalence in a large ASD population. PLoS ONE 8, e52239 (2013).
Moller, R. S. et al. Exon-disrupting deletions of NRXN1 in idiopathic generalized epilepsy. Epilepsia 54, 256–264 (2013).
Ching, M. S. L. et al. Deletions of NRXN1 (neurexin‐1) predispose to a wide spectrum of developmental disorders. Am. J. Med. Genet. B Neuropsychiatr. Genet. 153B, 937–947 (2010).
Huang, A. Y. et al. Rare copy number variants in NRXN1 and CNTN6 increase risk for Tourette syndrome. Neuron 94, 1101–1111.e7 (2017).
Grayton, H. M., Missler, M., Collier, D. A. & Fernandes, C. Altered social behaviours in neurexin 1α knockout mice resemble core symptoms in neurodevelopmental disorders. PLoS ONE 8, e67114 (2013).
Pak, C. et al. Human neuropsychiatric disease modeling using conditional deletion reveals synaptic transmission defects caused by heterozygous mutations in NRXN1. Cell Stem Cell 17, 316–328 (2015).
Pak, C. et al. Cross-platform validation of neurotransmitter release impairments in schizophrenia patient-derived NRXN1-mutant neurons. Proc. Natl Acad. Sci. USA 118, e2025598118 (2021).
Sebastian, R. et al. Schizophrenia-associated NRXN1 deletions induce developmental-timing- and cell-type-specific vulnerabilities in human brain organoids. Nat. Commun. 14, 3770 (2023).
Flaherty, E. et al. Neuronal impact of patient-specific aberrant NRXN1α splicing. Nat. Genet. 51, 1679–1690 (2019).
Boxer, E. E. & Aoto, J. Neurexins and their ligands at inhibitory synapses. Front. Synaptic Neurosci. 14, 1087238 (2022).
Sohal, V. S. & Rubenstein, J. L. R. Excitation–inhibition balance as a framework for investigating mechanisms in neuropsychiatric disorders. Mol. Psychiatry 24, 1248–1257 (2019).
Zhang, Y. et al. Rapid single-step induction of functional neurons from human pluripotent stem cells. Neuron 78, 785–798 (2013).
Yang, N. et al. Generation of pure GABAergic neurons by transcription factor programming. Nat. Methods 14, 621–628 (2017).
Li, Y. I. et al. Annotation-free quantification of RNA splicing using LeafCutter. Nat. Genet. 50, 151–158 (2018).
Iijima, T. et al. SAM68 regulates neuronal activity-dependent alternative splicing of neurexin-1. Cell 147, 1601–1614 (2011).
Iijima, T., Iijima, Y., Witte, H. & Scheiffele, P. Neuronal cell type-specific alternative splicing is regulated by the KH domain protein SLM1. J. Cell Biol. 204, 331–342 (2014).
Traunmuller, L., Gomez, A. M., Nguyen, T. M. & Scheiffele, P. Control of neuronal synapse specification by a highly dedicated alternative splicing program. Science 352, 982–986 (2016).
Traunmüller, L. et al. A cell-type-specific alternative splicing regulator shapes synapse properties in a trans-synaptic manner. Cell Rep. 42, 112173 (2023).
Virtanen, M. A., Uvarov, P., Mavrovic, M., Poncer, J. C. & Kaila, K. The multifaceted roles of KCC2 in cortical development. Trends Neurosci. 44, 378–392 (2021).
Willsey, H. R. et al. Parallel in vivo analysis of large-effect autism genes implicates cortical neurogenesis and estrogen in risk and resilience. Neuron 109, 1409 (2021).
Gegenhuber, B., Wu, M. V., Bronstein, R. & Tollkuhn, J. Gene regulation by gonadal hormone receptors underlies brain sex differences. Nature 606, 153–159 (2022).
Roberts, T. C., Langer, R. & Wood, M. J. A. Advances in oligonucleotide drug delivery. Nat. Rev. Drug Discov. 19, 673–694 (2020).
Saito, Y. et al. Differential NOVA2-mediated splicing in excitatory and inhibitory neurons regulates cortical development and cerebellar function. Neuron 101, 707–720.e5 (2019).
Paz, I., Kosti, I., Ares, M., Cline, M. & Mandel-Gutfreund, Y. RBPmap: a web server for mapping binding sites of RNA-binding proteins. Nucleic Acids Res. 42, W361–W367 (2014).
Ghanbarian, H., Aghamiri, S., Eftekhary, M., Wagner, N. & Wagner, K.-D. Small activating RNAs: towards the development of new therapeutic agents and clinical treatments. Cells 10, 591 (2021).
Subramanian, A. et al. A next generation connectivity map: L1000 platform and the first 1,000,000 profiles. Cell 171, 1437–1452.e17 (2017).
Yilmaz, C. et al. Neurosteroids as regulators of neuroinflammation. Front. Neuroendocrinol. 55, 100788 (2019).
Brunet De Courssou, J.-B., Durr, A., Adams, D., Corvol, J.-C. & Mariani, L.-L. Antisense therapies in neurological diseases. Brain 145, 816–831 (2022).
Ingusci, S., Verlengia, G., Soukupova, M., Zucchini, S. & Simonato, M. Gene therapy tools for brain diseases. Front. Pharmacol. 10, 724 (2019).
Lin, H.-C. et al. NGN2 induces diverse neuron types from human pluripotency. Stem Cell Rep. 16, 2118–2127 (2021).
Trotter, J. H. et al. Compartment-specific neurexin nanodomains orchestrate tripartite synapse assembly. Preprint at bioRxiv https://doi.org/10.1101/2020.08.21.262097 (2020).
Zafra, F. & Piniella, D. Proximity labeling methods for proteomic analysis of membrane proteins. J. Proteomics 264, 104620 (2022).
Bell, J. Stratified medicines: towards better treatment for disease. Lancet 383, S3–S5 (2014).
Tsimberidou, A. M. et al. Molecular tumour boards — current and future considerations for precision oncology. Nat. Rev. Clin. Oncol. 20, 843–863 (2023).
Zhang, H., Colclough, K., Gloyn, A. L. & Pollin, T. I. Monogenic diabetes: a gateway to precision medicine in diabetes. J. Clin. Invest. 131, e142244 (2021).
Sullivan, P. F. & Geschwind, D. H. Defining the genetic, genomic, cellular, and diagnostic architectures of psychiatric disorders. Cell 177, 162–183 (2019).
Gerasimavicius, L., Livesey, B. J. & Marsh, J. A. Loss-of-function, gain-of-function and dominant-negative mutations have profoundly different effects on protein structure. Nat. Commun. 13, 3895 (2022).
Wang, L. et al. Analyses of the autism-associated neuroligin-3 R451C mutation in human neurons reveal a gain-of-function synaptic mechanism. Mol. Psychiatry 29, 1620–1635 (2024).
Pinggera, A. et al. New gain-of-function mutation shows CACNA1D as recurrently mutated gene in autism spectrum disorders and epilepsy. Hum. Mol. Genet. 26, 2923–2932 (2017).
Clark, M. B. et al. Long-read sequencing reveals the complex splicing profile of the psychiatric risk gene CACNA1C in human brain. Mol. Psychiatry 25, 37–47 (2020).
Brunklaus, A. et al. Gene variant effects across sodium channelopathies predict function and guide precision therapy. Brain 145, 4275–4286 (2022).
Sanders, S. J. et al. Progress in understanding and treating SCN2A-mediated disorders. Trends Neurosci. 41, 442–456 (2018).
Kim, G., Gautier, O., Tassoni-Tsuchida, E., Ma, X. R. & Gitler, A. D. ALS genetics: gains, losses, and implications for future therapies. Neuron 108, 822–842 (2020).
Balendra, R. & Isaacs, A. M. C9orf72-mediated ALS and FTD: multiple pathways to disease. Nat. Rev. Neurol. 14, 544–558 (2018).
Prakasam, R. et al. LSD1/PRMT6-targeting gene therapy to attenuate androgen receptor toxic gain-of-function ameliorates spinobulbar muscular atrophy phenotypes in flies and mice. Nat. Commun. 14, 603 (2023).
Chintalaphani, S. R., Pineda, S. S., Deveson, I. W. & Kumar, K. R. An update on the neurological short tandem repeat expansion disorders and the emergence of long-read sequencing diagnostics. Acta Neuropathol. Commun. 9, 98 (2021).
Ho, S.-M. et al. Rapid Ngn2-induction of excitatory neurons from hiPSC-derived neural progenitor cells. Methods 101, 113–124 (2016).
Rhee, H. J. et al. An autaptic culture system for standardized analyses of iPSC-derived human neurons. Cell Rep. 27, 2212–2228.e7 (2019).
Barretto, N. et al. ASCL1- and DLX2-induced GABAergic neurons from hiPSC-derived NPCs. J. Neurosci. Methods 334, 108548 (2020).
Sloan, S. A., Andersen, J., Pașca, A. M., Birey, F. & Pașca, S. P. Generation and assembly of human brain region-specific three-dimensional cultures. Nat. Protoc. 13, 2062–2085 (2018).
Dobin, A. et al. STAR: ultrafast universal RNA-seq aligner. Bioinformatics 29, 15–21 (2013).
Liao, Y., Smyth, G. K. & Shi, W. featureCounts: an efficient general purpose program for assigning sequence reads to genomic features. Bioinformatics 30, 923–930 (2014).
Robinson, M. D., McCarthy, D. J. & Smyth, G. K. edgeR: a Bioconductor package for differential expression analysis of digital gene expression data. Bioinformatics 26, 139–140 (2010).
Hoffman, G. E. et al. Transcriptional signatures of schizophrenia in hiPSC-derived NPCs and neurons are concordant with post-mortem adult brains. Nat. Commun. 8, 2225 (2017).
Newman, A. M. et al. Determining cell type abundance and expression from bulk tissues with digital cytometry. Nat. Biotechnol. 37, 773–782 (2019).
Hoffman, G. E. & Schadt, E. E. variancePartition: interpreting drivers of variation in complex gene expression studies. BMC Bioinformatics 17, 483 (2016).
Ritchie, M. E. et al. limma Powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res. 43, e47 (2015).
Bray, N. L., Pimentel, H., Melsted, P. & Pachter, L. Near-optimal probabilistic RNA-seq quantification. Nat. Biotechnol. 34, 525–527 (2016).
Wu, T. et al. clusterProfiler 4.0: a universal enrichment tool for interpreting omics data. Innovation 2, 100141 (2021).
Seah, C. et al. Modeling gene × environment interactions in PTSD using human neurons reveals diagnosis-specific glucocorticoid-induced gene expression. Nat. Neurosci. 25, 1434–1445 (2022).
De Marinis, I., Lo Surdo, P., Cesareni, G. & Perfetto, L. SIGNORApp: a Cytoscape 3 application to access SIGNOR data. Bioinformatics 38, 1764–1766 (2022).
Stuart, T. et al. Comprehensive integration of single-cell data. Cell 177, 1888–1902.e21 (2019).
Urresti, J. et al. Cortical organoids model early brain development disrupted by 16p11.2 copy number variants in autism. Mol. Psychiatry 26, 7560–7580 (2021).
Yang, X. et al. Identification and validation of genes affecting aortic lesions in mice. J. Clin. Invest. 120, 2414–2422 (2010).
Birey, F. et al. Assembly of functionally integrated human forebrain spheroids. Nature 545, 54–59 (2017).
Kurtenbach, S. & Harbour, J. W. SparK: a publication-quality NGS visualization tool. Preprint at bioRxiv https://doi.org/10.1101/845529 (2019).
