Deficit of NMDA receptor activation in CA1 hippocampal area of aged rats is rescued by D-cycloserine

Activation of the glycine modulatory site of the N-methyl-D-aspartate glutamate receptor (NMDAR) may reduce cognitive impairments associated with normal ageing. In order to test this hypothesis, we assessed the effects of the partial agonist D-cycloserine (DCS) on cellular activities involved in memory formation. This was performed in CA1 cellular networks of adult and aged Sprague-Dawley rat hippocampal slices using extracellular field excitatory postsynaptic potential recordings. Synaptic potentials specifically mediated by NMDAR were significantly reduced in aged animals. DCS increased the magnitude of these responses in both adult and old rats but this effect was significantly higher in the latter, thus reversing the age-related decrease in NMDAR synaptic potentials. NMDAR-mediated theta burst long-term potentiation (TBS-LTP) as well as long-term depression (LTD) of synaptic transmission, prominent models for the cellular basis of learning and memory, were also weakened in aged animals. Age-related alterations of both forms of synaptic plasticity were rescued by DCS. In addition, the DCS-induced decrease in basal fast glutamatergic neurotransmission involving the activation of inhibitory glycinergic receptors, previously reported in young rats (Rouaud & Billard, 2003), was severely attenuated in aged animals. In summary, our results indicate that the facilitation of NMDAR activation through its glycine-binding site rescues the age-related deficit of cellular mechanisms of learning and memory. Such physiological evidences suggest that this modulation site of NMDAR represents an important target to alleviate cognitive deficits associated with normal ageing.