Retinal activity regulates developmental switches in functional properties and ifenprodil sensitivity of NMDA...

Previous studies have shown that marked changes occur in the kinetic properties of N-methyl-D-aspartate (NMDA) receptors during development of the visual pathways. In the lateral geniculate nucleus (LGN) of the ferret, excitatory postsynaptic currents (EPSCs) induced by activation of NMDA receptors display a very slow decay time during the first postnatal month, then become shorter in duration following eye-opening (around postnatal day 32; P32). In view of the critical role that NMDA receptors play in activity-dependent refinement of visual connections during development, we have examined the mechanisms that underlie these changes and how they are regulated. To examine the role of retinal activity, whole-cell recordings were conducted in the LGN slice preparation obtained from normal ferrets and ferrets treated with continuous intraocular application of tetrodotoxin (TTX) from P25 until the time of recording. Blockade of ganglion cell activity with TTX prevented the changes in decay rate of the postsynaptic current induced by NMDA receptors. Treated animals older than P40 had NMDA-EPSCs markedly longer in duration than normal animals at a similar age, resembling responses present in normal newborn animals. To examine whether changes in subunit composition of the NMDA receptor may contribute to the maturation of its kinetic properties, we used the antagonist ifenprodil, which produces selective inhibition of heteromeric NMDA receptors containing the NR-2B subunit. Ifenprodil induced profound inhibition of NMDA receptor activity in normal young animals and TTX-treated mature animals, but substantially less inhibition in normal mature animals. These findings indicate that retinal activity is required for the developmental switch from a juvenile form of the NMDA receptor to a more mature form, possibly affecting NR2 subunit expression.