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 neurons by Schaffer collaterals stimulation. In the presence of tetrodotoxin (TTX; 1 microM), 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 (1.5-1 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 microM). Chlorpheg enhanced also the NMDA component of the EPSP, evoked in the presence of 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX; 10 microM), bicuculline (20 microM) and glycine (100 microM). This effect was blocked by CPP (20 microM). It is concluded that L-HC is an endogenous NMDA agonist at the Schaffer collateral-CA1 synapse.