EFFECT OF CHRONIC ADMINISTRATION OF NMDA ANTAGONISTS ON SYNAPTIC DEVELOPMENT

The current research assessed the role of the N-methyl-D-aspartate (NM DA) receptor in developmental synaptic plasticity. This was accomplish ed by quantitative analysis of synaptic number and morphology followin g pharmacological manipulation of NMDA receptor activity using either the competitive antagonist 2-amino-5-phosphonovaleric acid (APV) or th e noncompetitive antagonist phencyclidine (PCP). In the first group, 1 5-day-old male Long-Evans rats were implanted with osmotic minipumps, which administered 50 mM APV or vehicle at a rate of 0.5 mu l per h in to the subjects' occipital cortex for 14 days. At age 30 days (P30), t he 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 synap ses. Similarly, PCP induced a reduction in brain weight, molecular lay er depth, and estimated total number of synapses. Withdrawal from NMDA antagonism was initially associated with similar results, i.e., reduc ed brain weight, cortex depth, synaptic density, and estimated total n umber of synapses, along with an increase in synaptic length. By P36, however, there was a transitory rebound associated with increased mole cular layer depth and estimated total number of synapses. These result s support the suggestion that NMDA receptor activation is integral to naturally occurring developmental synaptogenesis, and underscore the i mportance of NMDA receptor involvement in the process of synaptic plas ticity. (C) 1997 Wiley-Liss, Inc.