NMDA Receptor Currents Suppress Synapse Formation on Sprouting AxonsIn Vivo

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Abstract
NMDA receptors (NMDARs) play an important role in the structural maintenance and functional strength of synapses. The causal relationship between these anatomical and functional roles is poorly defined. Using quantitative confocal microscopy, synaptic vesicle immunoreactivity, and differential label of retinal projections, we measured axon volume and synapse density along ipsilateral retinal axons (ipsi axons) sprouting into the superficial visual layers of the superior colliculus (sSC) deafferented by a contralateral retinal lesion (a scotoma) 8 d earlier. When retinal lesions were made at postnatal day 6 (P6), glutamatergic synaptic currents on neurons within the scotoma were significantly reduced. Both ipsi axon sprouting and synapse density were increased by chronic d-AP-5 antagonism of NMDARs. Conversely, ipsi axon sprouting and synapse density were reduced by chronic exposure to the agonist, NMDA, known to functionally depress glutamate transmission in this system. After P11 lesions, however, NMDAR blockade had no effect on sprouting or synapse density. Developmental changes in NMDAR current kinetics could not account for this difference in the structural effects of NMDAR function. Also, synaptic current frequencies within the scotoma were not affected after the P11 lesions. The corticocollicular projection matures during the P11 survival interval and, as indicated by previous work, it is a source of competition for synaptic space and probably of maintained activity in the older sSC. Thus, our results suggest that during early development, NMDAR currents predominantly destabilize nascent synapses. As the neuropil matures, however, competition for synaptic space suppresses axon sprouting and synapse formation regardless of NMDAR function.