TY - JOUR
T1 - Cadherin-13 is a critical regulator of GABAergic modulation in human stem-cell-derived neuronal networks
AU - Mossink, Britt
AU - van Rhijn, Jon Ruben
AU - Wang, Shan
AU - Linda, Katrin
AU - Vitale, Maria R.
AU - Zöller, Johanna E.M.
AU - van Hugte, Eline J.H.
AU - Bak, Jitske
AU - Verboven, Anouk H.A.
AU - Selten, Martijn
AU - Negwer, Moritz
AU - Latour, Brooke L.
AU - van der Werf, Ilse
AU - Keller, Jason M.
AU - Klein Gunnewiek, Teun M.
AU - Schoenmaker, Chantal
AU - Oudakker, Astrid
AU - Anania, Alessia
AU - Jansen, Sophie
AU - Lesch, Klaus Peter
AU - Frega, Monica
AU - van Bokhoven, Hans
AU - Schubert, Dirk
AU - Nadif Kasri, Nael
N1 - Funding Information:
Funding This work was supported by Grants from: the Netherlands Organization for Scientific Research, NWO-CAS Grant 012.200.001 (to NNK); the Netherlands Organization for Health Research and Development ZonMw Grant 91217055 (to HvB); SFARI Grant 610264 (to NNK); the Dutch epilepsiefonds WAR 18-02 (to NNK); Horizon 2020 (Eat2beNICE) Grant 728018 (to KL); ERA-NET NEURON-102 SYNSCHIZ Grant (NWO) 013-17-003 4538 (to DS) and ERA-NET NEURON DECODE! Grant (NWO) 013.18.001 (to NNK) and (BMBF) 01EW1902 (to K-PL).
Publisher Copyright:
© 2021, The Author(s).
PY - 2022/1/1
Y1 - 2022/1/1
N2 - Activity in the healthy brain relies on a 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 patient, has typically been hampered by methodological limitations. Cadherin-13 (CDH13) has been associated with autism and attention-deficit/hyperactivity disorder. CDH13 localizes 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 MEF2C (PV-precursor marker protein) 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.
AB - Activity in the healthy brain relies on a 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 patient, has typically been hampered by methodological limitations. Cadherin-13 (CDH13) has been associated with autism and attention-deficit/hyperactivity disorder. CDH13 localizes 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 MEF2C (PV-precursor marker protein) 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.
UR - http://www.scopus.com/inward/record.url?scp=85105562364&partnerID=8YFLogxK
U2 - 10.1038/s41380-021-01117-x
DO - 10.1038/s41380-021-01117-x
M3 - Article
AN - SCOPUS:85105562364
SN - 1359-4184
VL - 27
SP - 1
EP - 18
JO - Molecular Psychiatry
JF - Molecular Psychiatry
ER -