Tunicamycin-induced unfolded protein response in the developing mouse brain

Area of Science:

• Neuroscience
• Cell Biology
• Developmental Biology

Background:

• Endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) are implicated in neurodevelopmental and neurodegenerative disorders.
• The developing brain is particularly vulnerable to environmental factors that can induce ER stress.

Purpose of the Study:

• To investigate the developmental regulation of the UPR in the postnatal mouse brain.
• To assess the susceptibility of the developing brain to ER stress-induced cell death.

Main Methods:

• Administration of tunicamycin, an ER stress inducer, to mice at postnatal days (PD) 4, 12, and 25.
• Evaluation of UPR markers (ATF6, XBP1s, p-eIF2α, GRP78, GRP94, MANF) and caspase-3 activation in brain regions and liver.
• Assessment of tunicamycin-induced cell death in cultured immature cerebellar neurons.

Main Results:

• Tunicamycin induced UPR in the cerebral cortex, hippocampus, and cerebellum of PD4 and PD12 mice, but not PD25 mice.
• Caspase-3 activation, indicative of cell death, was observed in the brains of PD4 and PD12 mice, with decreasing intensity and regional spread.
• UPR was induced in the liver at all stages, but caspase-3 activation was not observed in the liver.
• Immature cerebellar neurons in culture were sensitive to tunicamycin-induced cell death, while mature neurons became resistant.

Conclusions:

• The unfolded protein response in the brain is developmentally regulated.
• The immature brain is more susceptible to ER stress and subsequent cell death compared to the mature brain.
• These findings highlight the critical window of vulnerability in brain development concerning ER stress.