Memantine restores long term potentiation impaired by tonic N-methyl-D-aspartate (NMDA) receptor activation following reduction of Mg2+ in hippocampal slices.

This study compared the ability of memantine and (+)MK-801 to counteract deficits in the induction of long term potentiation (LTP) following reduction of Mg2+ in hippocampal slices--a model of increased synaptic noise due to tonic N-methyl-D-aspartate (NMDA) receptor activation. Decreasing Mg2+ from 1 mM to 10 microM for 60 min enhanced baseline field excitatory post-synaptic potential (fEPSP) slopes (87.2 +/- 10.6% above control) and impaired LTP (-4.1 +/- 9.8% compared to pre-tetanic levels). Long pre-incubations with memantine (1 microM), a concentration achieved in the CSF of dementia patients, almost fully restored the induction of LTP (to 43.4 +/- 8.4%) without changing the enhancement of baseline fEPSP slopes (84.1 +/- 11.6%). Memantine (10 microM) fully restored the induction of LTP (61.5 +/- 5.3%) and also decreased the enhancement of baseline fEPSP slopes (30.1 +/- 4.9%). In contrast, although (+)MK-801 (0.01, 0.1 and 1 microM) caused a concentration-dependent reduction in the low Mg2+ -induced enhancement of baseline fEPSP slopes, it was not able to restore the induction of LTP (3.0 +/- 9.8%, 16.3 +/- 5.7% and 4.8 +/- 6.7% respectively). These data indicate that memantine could produce symptomatological improvement in learning under conditions of tonic NMDA receptor activation such as those occurring in chronic neurodegenerative diseases whereas (+)MK-801 is likely to have only negative effects.