ESPE Yearbook of Paediatric Endocrinology

Sci Rep. 2021 Nov 3;11(1):21590. doi: 10.1038/s41598-021-00939-7. PMID: 34732776.

Brief Summary: This study describes the molecular and electrophysiological analysis of the cerebral network generated from cerebral organoids from human induced pluripotent stem cells (hiPSCs) on a patient with neonatal diabetes mellitus due to a KCNJ11 mutation.

Some patients with permanent neonatal diabetes mellitus (PNDM) due to activating KCNJ11 (KATP channel subunit) gene mutations have neurological deficits such as severe learning disorders, cognitive disorders such as autism spectrum like disorder and epilepsy. KATP channels also play a role in coupling neuronal metabolism to electrical excitability and neurotransmitter release and this influences the development of neuronal circuits during neurogenesis. Advances in human induced pluripotent stem cell and 3D cell culture technology have made it possible to generate brain tissue called cerebral organoids, in vitro (1). Cerebral organoid technology provides a good model for understanding neural differentiation as well as the effects of genetic variation on gene expression of brain development and disease.

The mechanisms of the learning disorders and cognitive disorders, such as autism spectrum-like disorder and epilepsy due to activating KCNJ11 mutations is/are not clear. So, in order to understand the electrophysiological role of the KNCJ11 mutation (V59M) in the cerebral network, the authors created first an iPSC line from a patient with PNDM. They then converted the iPSC into cerebral organoids and studied the electrophysiology of the neuronal networks. The mutant organoid showed impaired neurodevelopment, and impaired neuronal differentiation with defects in the laminar organization of the neocortex development. The decreased neurogenesis resulted in defective neural circuit formation and activity with failure to migrate and differentiate normally. Interestingly pharmacological treatment with tolbutamide (sulphonylurea which blocks the KATP channel) partially rescued the molecular defects caused by hyperpolarization of the cell membrane.

Overall, these findings suggest that the mutant KCNJ11 channel activity dysregulates neuronal circuit formation and neuronal network excitability in human cerebral samples. The study was able to disentangle the confounding effects of neonatal diabetes mellitus from the direct influence of the V59M mutation on neural precursors and neurons. This study provides the first evidence that a mutant KCNJ11 channel directly causes neurological deficits in patient hiPSC derived brain tissue.

Reference: 1. Lancaster, MA, Knoblich, JA. Organogenesis in a dish: Modeling development and disease using organoid technologies. Science (New York, NY) 345, 1247125 (2014).