N-methyl-D-aspartate receptor blockade affects polysialylated neural cell adhesion molecule expression and synaptic...

Glutamatergic neurons innervate the striatum and form asymmetric synapses with the dendritic spines of striatal efferent neurons. The role of glutamate in striatal development, however, remains largely unknown. Previous studies have shown a dramatic increase in the density of asymmetric synapses in the rat striatum during the third postnatal week, followed by a decrease to adult levels by postnatal day 25. At the same time, the highly polysialylated form of the neural cell adhesion molecule becomes progressively restricted to synaptic regions and then disappears. We have now examined the effects of antagonists of the N-methyl-D-aspartate subtype of glutamatergic receptors on the expression of the polysialylated form of the neural cell adhesion molecule and on synaptic density during this late period of striatal development. Peripheral administration of the N-methyl-D-aspartate receptor antagonist dizocilpine maleate markedly decreased immunoreactivity for the highly polysialylated form of the neural cell adhesion molecule in the dorsolateral striatum and cerebral cortex when drug treatment included postnatal day 20, but not earlier in development. This effect was regionally specific and loss of the polysialylated neural cell adhesion molecule in the striatum was reproduced by the local administration of dizocilpine maleate, DL-2-amino-5-phosphonovalerate or ketamine on postnatal day 20. Quantitative ultrastructural studies of synaptic density with the physical disector method performed after one of the regimens inducing loss of the polysialylated neural cell adhesion molecule (postnatal days 18-20) revealed a 30% decrease in asymmetric synapses in the dorsolateral striatum of treated rats. Symmetric synapses, which presumably do not use glutamate, were not affected. The data indicate that N-methyl-D-aspartate receptors play a role in the late stages of synaptogenesis in the striatum and suggest that a subset of synapses expressing immunoreactivity for the highly polysialylated form of the neural cell adhesion molecule may be dependent on N-methyl-D-aspartate receptor stimulation during a critical period of striatal development.