eprintid: 10169882 rev_number: 12 eprint_status: archive userid: 699 dir: disk0/10/16/98/82 datestamp: 2023-05-15 08:05:18 lastmod: 2023-10-31 13:51:24 status_changed: 2023-05-15 08:05:18 type: article metadata_visibility: show sword_depositor: 699 creators_name: St George-Hyslop, Frances creators_name: Haneklaus, Moritz creators_name: Kivisild, Toomas creators_name: Livesey, Frederick J title: Loss of CNTNAP2 Alters Human Cortical Excitatory Neuron Differentiation and Neural Network Development ispublished: pub divisions: UCL divisions: B02 divisions: D13 divisions: G22 keywords: Cerebral cortex, CNTNAP2, Development, Network, formation, Neurogenesis, Stem cells note: © 2023 Society of Biological Psychiatry. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). abstract: BACKGROUND: Loss-of-function mutations in the contactin-associated protein-like 2 (CNTNAP2) gene are causal for neurodevelopmental disorders, including autism, schizophrenia, epilepsy and intellectual disability. CNTNAP2 encodes CASPR2, a single-pass transmembrane protein that belongs to the neurexin family of cell adhesion molecules. These proteins have a variety of functions in developing neurons, including connecting presynaptic and postsynaptic neurons, and mediating signalling across the synapse. METHODS: To study the effect of loss of CNTNAP2 function on human cerebral cortex development, and how this contributes to the pathogenesis of neurodevelopmental disorders, we generated human iPSCs from one neurotypical control donor null for full-length CNTNAP2, modelling cortical development from neurogenesis through to neural network formation in vitro. RESULTS: CNTNAP2 is particularly highly expressed in the first two populations of early-born excitatory cortical neurons, and loss of CNTNAP2 shifted the relative proportions of these two neuronal types. Live imaging of excitatory neuronal growth showed that loss of CNTNAP2 reduced neurite branching and overall neuronal complexity. At the network level, developing cortical excitatory networks null for CNTNAP2 had complex changes in activity compared to isogenic controls: an initial period of relatively reduced activity compared with isogenic controls, followed by a lengthy period of hyperexcitability, and then a further switch to reduced activity. CONCLUSIONS: Complete loss of CNTNAP2 contributes to the pathogenesis of neurodevelopmental disorders through complex changes in several aspects of human cerebral cortex excitatory neuron development that culminate in aberrant neural network formation and function. date: 2023-11-15 date_type: published publisher: Elsevier BV official_url: http://doi.org/10.1016/j.biopsych.2023.03.014 oa_status: green full_text_type: pub language: eng primo: open primo_central: open_green verified: verified_manual elements_id: 2014803 doi: 10.1016/j.biopsych.2023.03.014 medium: Print-Electronic pii: S0006-3223(23)01165-4 lyricists_name: Livesey, Frederick lyricists_id: FLIVE31 actors_name: Flynn, Bernadette actors_id: BFFLY94 actors_role: owner full_text_status: public publication: Biological Psychiatry volume: 94 number: 10 pagerange: 780-791 event_location: United States issn: 0006-3223 citation: St George-Hyslop, Frances; Haneklaus, Moritz; Kivisild, Toomas; Livesey, Frederick J; (2023) Loss of CNTNAP2 Alters Human Cortical Excitatory Neuron Differentiation and Neural Network Development. Biological Psychiatry , 94 (10) pp. 780-791. 10.1016/j.biopsych.2023.03.014 <https://doi.org/10.1016/j.biopsych.2023.03.014>. Green open access document_url: https://discovery.ucl.ac.uk/id/eprint/10169882/1/Livesey_1-s2.0-S0006322323011654-main.pdf