Disruption of experience-dependent synaptic modifications in striate cortex by infusion of an NMDA receptor antagonist

Abstract

To assess the possibility that NMDA receptors play a special role in visual cortical plasticity, the selective antagonist 2-amino-5- phosphonovaleric acid (APV) was continuously infused into the striate cortex of kittens as the visual environment was manipulated during the critical period. The cortex was studied using single-unit recording from sites between 3 and 6 mm from the infusion cannulae. One week of D,L-APV infusion coincident with monocular deprivation or “reverse suture” produced a concentration-dependent increase in the percentage of neurons that (1) lacked normal orientation selectivity and (2) were responsive to stimulation of the deprived eye. These effects outlasted the presence of the drug in the tissue. APV treatment also prevented the acquisition of selectivity and visual responsiveness that normally results from monocular visual experience after dark-rearing. Lasting effects of chronic APV infusion were not observed in adult striate cortex. The effects of APV on kitten striate cortex depended on the presence of the D stereoisomer as infusion of L-APV was without effect. Estimates of extracellular concentration using 3H-APV indicated that significant effects could be obtained with concentrations as low as 20 microM D,L-APV. Recordings from units during infusion indicated that visual responses were reduced by APV. Nonetheless, a normal percentage of visually responsive neurons was found at sites greater than or equal to 3 mm from the infusion cannula. There was no evidence that chronic APV infusion affected the sampling frequency of recorded neurons or disrupted cytoarchitecture at the sites further than 3 mm from the infusion cannula. Taken together, the data indicate that the effects of APV on kitten striate cortex are likely due specifically to the blockade of NMDA receptors. These data are considered in relation to several hypotheses concerning the role of NMDA receptors in the experience-dependent development of striate cortex.

A Role for Nitric Oxide in the Development of the Ferret Retinogeniculate Projection

“…Our results in the ferret LGN contrast with studies of cat visual cortex, in which ocular dominance plasticity requires NMDA receptor activation (Bear et al, 1990) but does not seem to require NO (Gillespie et al, 1993;Daw et al, 1994). Consistent with this difference, NADPH-diaphorase staining is developmentally regulated in LGN neurons but not in visual cortical neurons.…”

Acceleration of Visual System Development by Environmental Enrichment

“…Indeed, enrichment in the adult causes changes in the NMDA receptor expression and in the expression of downstream molecules (Rampon et al, 2000;Molteni et al, 2002). NMDA receptors have been demonstrated to play a crucial role in ocular dominance plasticity and in development of receptive field properties in the visual cortex (Bear et al, 1990;Roberts et al, 1998;Ramoa et al, 2001;Fagiolini et al, 2003) and to be highly sensitive to activity (Quinlan et al, 1999;Philpot et al, 2001). Interestingly, Liu et al (2000) have shown that maternal care affects NMDAR subunit expression in the hippocampus.…”

Hypothermic neuroprotection

“…172 NMDA receptor blockade impairs induction of long-term potentiation (LTP) which is important for memory formation. 173 In addition, MK-801 causes acute but reversible neuronal vacuolization when systemically administered at neuroprotective doses in adult rodents. 174 Even more concerning, in the developing brain NMDA antagonists such as MK-801 have long lasting effects on neuronal circuits, 175 can trigger widespread apoptotic neurodegeneration in the developing brain 176 and indeed while MK-801 after head injury protected against primary necrotic damage it actually increased severity of secondary apoptotic damage.…”