Modeling ASD-linked genetic mutations in 3D human brain organoids

Summary

This project aims to investigate the impact of the ASD-linked CHD8 genetic mutation on neuronal development and circuit activity, specifically focusing on GABAergic neurons, using advanced 3D human brain organoid models.

What they want

The project will leverage expertise in organoid biology and cortical development, along with human cortical physiology, to investigate the effect of heterozygous loss-of-function of CHD8 on neuronal development and circuit activity. Aim 1 involves applying a chimeric organoid ("chimeroid") model to understand if the genetic context of ASD patients is permissive for expressivity of CHD8+/- phenotypes. Aim 2 will use a new human organoid model of the ventral telencephalon to determine if specific classes of GABAergic interneurons are preferentially affected by CHD8 mutation. Aim 3 will apply a new "dorsal-ventral chimeroid" organoid model to investigate cell identity and circuit activity in the CHD8 heterozygous mutant in a more physiologically-relevant system, utilizing calcium imaging, extracellular recording, and pharmacological manipulations.

Deliverables

Mechanistic understanding of the roles of CHD8 in the formation of GABAergic neuron populations of the cerebral cortex
Mechanistic understanding of CHD8's role in the biology of cortical circuits
Data on CHD8+/- phenotypes in various genetic contexts using chimeroid models
Identification of specific GABAergic interneuron classes affected by CHD8 mutation
Data on cell identity and circuit activity in CHD8 heterozygous mutants using dorsal-ventral chimeroids

Technical requirements

Human cortical organoid model
Chimeric organoid ("chimeroid") model
Human organoid model of the ventral telencephalon
Dorsal-ventral chimeroid organoid model
Calcium imaging
Extracellular recording
Pharmacological manipulations

Key personnel

Expertise in organoid biology and cortical development
Co-Investigator Mark Harnett (expertise in human cortical physiology)

Risks & flags

Incumbent: Current research team (unnamed PI) and Co-Investigator Mark Harnett