Chronic neonatal N-methyl-D-aspartate receptor antagonism with MK-801 increases the number of corticospinal cells retained into adulthood in the rat.

The corticospinal tract elaborates and matures from an initial imprecise and wide spread projection to the more limited pattern seen in adult animals. This cortical projection to the spinal cord is refined through the elimination of 'inappropriate' axons. In the present experiments on the developmental shaping of corticospinal connections, an effect was observed after treatment with a non-competitive antagonist of the N-methyl-D-aspartate (NMDA) receptor. Rat pups were exposed to the NMDA receptor antagonist MK-801 daily from the first to third postnatal week; littermates were injected with 0.9% saline and served as controls. At 4 weeks of age, animals were anesthetized, and Fast blue was inserted into the corticospinal tract at the 4th cervical segment of the spinal cord. The number of cortical neurons labeled with Fast blue was counted and compared between the two groups. MK-801 treated animals were smaller than their littermate controls. The results support the following conclusions: (1) the total number of cortical cells labeled from the cervical spinal cord placement was significantly increased (> 25%; P < 0.0005) in those animals who received MK-801 daily; and (2) the greatest increases of labeled cells were seen in the frontal and occipital cortices. These data emphasize the significance of the NMDA receptor in the shaping of central nervous system projections, and supports the use of the corticospinal projection as a model of development for glutamatergic connections.