PgmNr Z6221: A Novel Developmental Requirement for NMDA Receptors in Axon Guidance is Disrupted by Hypoxic Injury.

Authors:
J. Gao; T. Stevenson; J. Bonkowsky


Institutes
Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, UT.


Abstract:

Hypoxic injury in the developing human brain is a major cause of chronic neurodevelopmental impairments in part through loss of normal connectivity although the mechanisms are poorly understood. Here we found that hypoxic injury down-regulates N-methyl-D-aspartate receptors (NMDAR) expression in the developing brain. NMDARs are glutamate-gated heteromeric ion channels widely expressed in the CNS that play key roles in excitatory synaptic transmission in the adult brain and in synapse stabilization. We found that commissural pathfinding is disrupted by pharmacological inhibition of NMDARs. We demonstrate that the NMDAR NR1 subunit is expressed in commissural axons, and that vglut1, the biosynthesis enzyme for glutamate, is expressed in neurons adjacent to the commissural axons. We further show that NMDAR agonist can rescue the hypoxic-induced commissural neuron pathfinding defects. In summary, we report an unexpected developmental role for NMDARs in axon pathfinding, and show that disruption of normal NMDAR function by hypoxia contributes to connectivity disruption.