Caged glutamate induces HCY-reducible desensitization in hippocampal cultures. UV uncaging of 1 mM 4-methoxy-7-nitroindolinyl (MNI)-caged glutamate strongly desensitized NMDAR currents in DIV11 cultured hippocampal neurons (200 nM bathing GLY). Homocysteic acid (HCA; 10 μM), an active agent at the NMDAR glutamate site, induced NMDAR currents of similar amplitude to 1 mM HCY. However, instead of enhancing charge transfer, HCA greatly damped the response to glutamate uncaging (91% reduction of charge transfer, P ≤ 0.05, N = 3). Washout of HCA lead to restoration of a desensitizing response to glutamate uncaging. Desensitization was, in turn, strongly reduced by 1 mM HCY on the same cell (49% enhancement of normal charge transfer, P ≤ 0.05). Therefore, the effects of HCY and HCA are separate, and it is unlikely that metabolic conversion of HCY to HCA that could occur in hippocampal slices is a source of HCY's charge transfer enhancement.