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Developmental defects and impaired network excitability in a cerebral organoid model of KCNJ11 p.V59M-related

Gokhan Dalgin1, Andrew K Tryba2, Ashley P Cohen3

  • 1Section of Endocrinology, Diabetes and Metabolism, Departments of Medicine and Pediatrics, Kovler Diabetes Center, The University of Chicago, Chicago, IL, USA. gdalgin@gmail.com.

Scientific Reports
|November 4, 2021
PubMed

Insights

Mutations in the KCNJ11 gene cause neonatal diabetes and neurological issues. Human cerebral organoids reveal KCNJ11 mutations impair neural network development and synchronization, offering insights into brain dysfunction.

Area of Science:

  • Neuroscience
  • Genetics
  • Developmental Biology

Background:

  • The KCNJ11 gene encodes Kir6.2, a key subunit of ATP-sensitive potassium (KATP) channels.
  • Gain-of-function mutations in KCNJ11 are linked to neonatal diabetes mellitus (NDM) and diverse neurological defects.
  • The precise contribution of mutant KATP channels to brain dysfunction remains incompletely understood.

Purpose of the Study:

  • To investigate the neurodevelopmental impact of the KCNJ11 p.Val59Met (V59M) mutation using human cerebral organoids.
  • To explore the functional consequences of KCNJ11 mutations on neural network activity and cortical development.
  • To assess the therapeutic potential of KATP channel blockers in mitigating mutation-related neurodevelopmental deficits.

Main Methods:

  • Generation of cerebral organoids from human induced pluripotent stem cells (hiPSCs) with and without the KCNJ11 V59M mutation.
  • Electrophysiological recordings to assess neuronal network synchronization and bursting activity.
  • Histocytochemical analysis to evaluate neuronal distribution and cortical layer formation.
  • Transcriptional profiling of neural stem cell markers, including SOX2.
  • Pharmacological treatment with the KATP channel blocker tolbutamide.

Main Results:

  • V59M cerebral organoids exhibited reduced neuronal network synchronization compared to controls.
  • A significant reduction in neurons within upper cortical layer-like structures was observed in V59M organoids.
  • An extended expression window of the neural stem cell marker SOX2 was detected in V59M organoids.
  • Tolbutamide treatment partially rescued the observed neurodevelopmental abnormalities in V59M organoids.

Conclusions:

  • Human cerebral organoids serve as a valuable model for studying KCNJ11-associated neurodevelopmental disorders.
  • KCNJ11 mutations directly impair cortical neuronal network development and synchronization.
  • Targeting KATP channels may offer a therapeutic strategy for neurological complications in NDM patients.

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