The role of N-methyl-D-aspartate receptors in neuronal plasticity of the primary visual cortex

Neuronal plasticity is a subject of great interest in current neurobiology because of its role in development, response to injury, and the phenomena of learning and memory. One of the most intensely studied models of neocortical plasticity is the mammalian visual cortex. Interruption of the visual input to one eye during a critical period of development leads to the loss of connections relaying information from the deprived eye to the visual cortex. It has been proposed that the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor plays a major role in this type of neuronal plasticity. However, previous experiments addressing this hypothesis have not determined whether NMDA receptors have an instructive or a permissive function in visual cortical plasticity. We have addressed two questions regarding this issue.; 1. Do NMDA receptors have a critical function in visual plasticity? To address this question, knockdown experiments were performed using antisense oligodeoxynucleotides (ODNs) complementary to the mRNA encoding the NR1 subunit of the NMDA receptor. This treatment reduced NMDA receptor activity by specifically reducing expression of NR1 subunits, which are required for normal NMDA receptor function. The resultant reduction in NMDA receptor function blocked ocular dominance plasticity following monocular deprivation. Importantly, visual response properties remained unaltered by the treatment providing unambiguous evidence for a specific role of NMDA receptors in visual plasticity.; 2. Do ontogenetic changes in the NMDA receptor contribute to the determination of the critical period of visual plasticity? The NMDA receptor is known to exhibit marked changes in subunit composition and functional properties during neural development. We have examined the timecourse of NMDA receptor changes during normal development and how they correlate with the critical period of ocular dominance plasticity in the ferret. We have found evidence that molecular changes leading to shorter duration NMDA receptor excitatory post-synaptic currents may be a requirement for the onset of the critical period of ocular dominance plasticity. The results presented here provide strong evidence for an instructive role of NMDA receptors in visual plasticity and show that antisense techniques can be used in further investigations into the physiological functions of NMDA receptors.