L-homocysteic acid mediates synaptic excitation at NMDA receptors in the hippocampus

Beta-p-Chlorophenylglutamate (Chlorpheg), a specific L-homocysteate (L-HC) uptake blocker, was tested on the L-HC- and L-glutamate-induced currents and on the excitatory postsynaptic potentials (EPSPs) evoked in CA1 rat hippocampal neurones by Schaffer collaterals stimulation. In the presence of tetrodotoxin (TTX; 1-mu-M), Chlorpheg (0.5-2 mM) potentiated L-HC- but not L-glutamate-induced currents. In normal magnesium containing medium and at resting membrane potential, Chlorpheg (0.5-1 mM) increased the amplitude and duration of the EPSPs evoked by Schaffer collaterals stimulation. This effect was prevented by bath application of the N-methyl-D-aspartate (NMDA) receptor antagonist CPP (20-mu-M). Chlorpheg enhanced also the NMDA component of the EPSP, evoked in the presence of 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX; 10-mu-M), bicuculline (20-mu-M) and glycine (100-mu-M). This effect was blocked by CPP (20-mu-M). It is concluded that L-HC is an endogenous NMDA agonist at the Schaffer collateral-CA1 synapse.