Cell-type specific defects in PTEN-mutant cortical organoids converge on abnormal circuit activity

Area of Science:

• Neuroscience
• Developmental Biology
• Genetics

Background:

• Heterozygous loss-of-function mutations in phosphatase and tensin homolog (PTEN) are linked to autism spectrum disorders.
• The precise impact of these PTEN mutations on distinct cell types during human brain development and individual variability remains unclear.

Purpose of the Study:

• To investigate cell-type specific developmental effects of heterozygous PTEN mutations in human cortical organoids.
• To understand how donor genetic background influences these developmental abnormalities.
• To examine the consequences of these mutations on neuronal circuit activity.

Main Methods:

• Utilized human cortical organoids from multiple donors.
• Employed single-cell RNA-sequencing, proteomics, and spatial transcriptomics for comprehensive profiling.
• Conducted calcium imaging in intact organoids to assess neuronal circuit function.

Main Results:

• Identified abnormalities in developmental timing affecting outer radial glia progenitors and deep-layer cortical projection neurons.
• Observed that these developmental phenotypes varied depending on the donor's genetic background.
• Found that both accelerated and delayed neuronal development led to similar disruptions in local circuit activity, irrespective of genetic background.

Conclusions:

• Heterozygous PTEN mutations induce donor-dependent, cell-type specific developmental phenotypes during human brain development.
• These distinct cellular effects converge to disrupt neuronal activity in the developing brain.
• This study provides insights into the cellular and circuit-level mechanisms underlying PTEN-associated neurodevelopmental disorders.