Microglia regulate GABAergic neurogenesis in prenatal human brain through IGF1

Area of Science:

• Neuroscience
• Developmental Biology
• Neuroimmunology

Background:

• GABAergic neurons are crucial for human cognitive abilities.
• The mechanisms driving increased GABAergic neuron production in the human brain are not fully understood.
• Microglia, the brain's immune cells, play roles in neural development.

Purpose of the Study:

• To investigate microglial regulation of GABAergic neuron progenitor proliferation in the human medial ganglionic eminence (hMGE).
• To identify molecular mechanisms of microglia-progenitor communication in the developing human brain.

Main Methods:

• Utilized novel neuroimmune hMGE organoids mimicking human brain development.
• Analyzed microglia distribution and identified ligand-receptor interactions (IGF1/IGF1R).
• Investigated the functional role of microglia-derived IGF1 using neutralizing antibodies and gene knockout.

Main Results:

• Microglia are concentrated in the hMGE's proliferative zones.
• Insulin-like growth factor 1 (IGF1) signaling between microglia and progenitors was identified.
• Microglia-derived IGF1 significantly promoted GABAergic progenitor proliferation and neuron production.
• Blocking IGF1 or removing it from microglia abolished proliferation.

Conclusions:

• Microglia play a critical role in the sustained proliferation of human GABAergic neuron progenitors.
• Microglia-derived IGF1 is a key signaling molecule mediating this effect.
• This study reveals a novel neuroimmune mechanism essential for human brain development and cognitive capacity.