Effect of chronic administration of NMDA antagonists on synaptic development

The current research assessed the role of the N-methyl-D-aspartate (NMDA) receptor in developmental synaptic plasticity. This was accomplished by quantitative analysis of synaptic number and morphology following pharmacological manipulation of NMDA receptor activity using either the competitive antagonist 2-amino-5-phosphonovaleric acid (APV) or the noncompetitive antagonist phencyclidine (PCP). In the first group, 15-day-old male Long-Evans rats were implanted with osmotic minipumps, which administered 50 mM APV or vehicle at a rate of 0.5 microliter per h into the subjects' occipital cortex for 14 days. At age 30 days (P30), the rats were sacrificed and their occipital neocortices were examined. A second group of rats was given subcutaneous injections of 10 mg/kg PCP or vehicle once daily beginning on P5 for a period of 15 days, and was sacrificed on P20. To determine the effects following withdrawal from long-term NMDA antagonism, a third group of animals was given the same PCP injection routine until P20, but was sacrificed on P21, P26, P36, and P56. Developmental administration of APV was associated with a decreased molecular layer depth and estimated total number of synapses. Similarly, PCP induced a reduction in brain weight, molecular layer depth, and estimated total number of synapses. Withdrawal from NMDA antagonism was initially associated with similar results, i.e., reduced brain weight, cortex depth, synaptic density, and estimated total number of synapses, along with an increase in synaptic length. By P36, however, there was a transitory rebound associated with increased molecular layer depth and estimated total number of synapses. These results support the suggestion that NMDA receptor activation is integral to naturally occurring developmental synaptogenesis, and underscore the importance of NMDA receptor involvement in the process of synaptic plasticity.