Ontogeny of AMPA and NMDA receptor gene expression in the developing sheep white matter and cerebral cortex

Area of Science:

• Neuroscience
• Developmental Biology
• Perinatal Medicine

Background:

• White matter injury is common in premature infants.
• Glutamate receptors, particularly alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, are implicated in excitotoxicity.
• Calcium-permeable AMPA receptors may contribute to brain damage.

Purpose of the Study:

• To test the hypothesis linking white matter injury in premature infants to increased calcium-permeable AMPA receptors.
• To characterize AMPA and N-methyl-d-aspartate (NMDA) receptor subunit expression in ovine fetal white matter and cortex during development.

Main Methods:

• Examined AMPA and NMDA receptor subunit expression in ovine fetal white matter and cerebral cortex at various gestational ages (0.5, 0.65, 0.85, and term).
• Quantified relative and absolute expression of AMPA receptor subunits, focusing on the calcium-impermeable GluR2 subunit.

Main Results:

• Subcortical white matter consistently showed low expression of the calcium-impermeable AMPA receptor GluR2 subunit relative to other subunits throughout gestation.
• In contrast, cerebral cortex showed decreased GluR2 mRNA but increased protein expression with advancing gestation.
• These patterns indicate a potential vulnerability of white matter to AMPA receptor-mediated calcium toxicity.

Conclusions:

• The initial hypothesis requires revision as white matter's low GluR2 expression suggests a different mechanism than previously assumed.
• Findings suggest AMPA receptor-mediated glutamate toxicity may not be the primary driver of brain damage in premature infants.
• Ovine model provides insights into developmental changes in glutamate receptor expression and potential excitotoxicity vulnerabilities.