TY - JOUR T1 - Cadherin-13 is a critical regulator of GABAergic modulation in human stem cell derived neuronal networks JF - bioRxiv DO - 10.1101/2020.05.07.082453 SP - 2020.05.07.082453 AU - Britt Mossink AU - Jon-Ruben van Rhijn AU - Shan Wang AU - Eline J. H. van Hugte AU - Katrin Linda AU - Jitske Bak AU - Anouk H. A. Verboven AU - Martijn Selten AU - Alessia Anania AU - Sophie Jansen AU - Jason M. Keller AU - Teun Klein Gunnewiek AU - Chantal Schoenmaker AU - Astrid Oudakker AU - Monica Frega AU - Hans van Bokhoven AU - Dirk Schubert AU - Nael Nadif Kasri Y1 - 2020/01/01 UR - http://biorxiv.org/content/early/2020/05/07/2020.05.07.082453.abstract N2 - Activity in the healthy brain relies on concerted interplay of excitation (E) and inhibition (I) via balanced synaptic communication between glutamatergic and GABAergic neurons. A growing number of studies imply that disruption of this E/I balance is a commonality in many brain disorders, however, obtaining mechanistic insight into these disruptions, with translational value for the human patient, has typically been hampered by methodological limitations. Cadherin-13 (CDH13) has strongly been associated to attention-deficit/hyperactivity disorder and comorbid disorders such as autism and schizophrenia. CDH13 localises at inhibitory presynapses, specifically of parvalbumin (PV) and somatostatin (SST) expressing GABAergic neurons. However, the mechanism by which CDH13 regulates the function of inhibitory synapses in human neurons remains unknown. Starting from human induced pluripotent stem cells, we established a robust method to generate a homogenous population of SST and PV expressing GABAergic neurons (iGABA) in vitro, and co-cultured these with glutamatergic neurons at defined E/I ratios on micro-electrode arrays. We identified functional network parameters that are most reliably affected by GABAergic modulation as such, and through alterations of E/I balance by reduced expression of CDH13 in iGABAs. We found that CDH13-deficiency in iGABAs decreased E/I balance by means of increased inhibition. Moreover, CDH13 interacts with Integrin-β1 and Integrin-β3, which play opposite roles in the regulation of inhibitory synaptic strength via this interaction. Taken together, this model allows for standardized investigation of the E/I balance in a human neuronal background and can be deployed to dissect the cell-type specific contribution of disease genes to the E/I balance.Competing Interest StatementThe authors have declared no competing interest. ER -