Comparison of responses to transmitter candidates at an N-methylaspartate receptor mediated synapse, in slices of rat cerebral cortex.

Intracellular recordings from pyramidal neurones in isolated slices of rat cerebral cortex allowed a comparison of postsynaptic potentials and responses to electrophoretic application of excitatory amino acids. The responses of all neurones to N-methylaspartate displayed an unusual voltage relation and were associated with an apparent increase in membrane resistance, properties that were dependent on the presence of extracellular Mg2+. Responses to N-methylaspartate could be elicited only when the electrophoretic pipette was positioned close to the cell soma and were associated with generation of slow spikes which triggered bursts of fast spikes. In contrast, in the majority of neurones, responses to glutamate, aspartate, cysteate and cysteine sulphinate demonstrated a conventional voltage relation, were associated with a decrease in membrane resistance, evoked no slow spikes, were insensitive to extracellular Mg2+ concentrations between 1 and near 0 mM and could be evoked with small currents of amino acids when the electrophoretic pipette was greater than 100 micron from the cell soma. Responses to the five amino acids were tested with the N-methylaspartate antagonist 2-amino-5-phosphonovaleric acid. In the majority of cells, this antagonist blocked responses to N-methylaspartate at doses that had only a small effect on responses to the other amino acids. In these experiments it was also possible to confirm previous reports that ketamine and cyclazocine act as selective N-methylaspartate antagonists. In 4/63 neurones, responses to glutamate and aspartate and in 1/5 neurones one component of the response to cysteate, displayed properties similar to those of responses to N-methylaspartate. In one other neurone, large applications of cysteine sulphinate or glutamate could evoke slow spikes and fast spike bursts, a firing pattern that was sensitive to 2-amino-5-phosphonovalerate. The present experiments therefore demonstrate that all four naturally occurring amino acids tested can activate N-methylaspartate receptors and indicate that any one of these could be the transmitter at the N-methylaspartate receptor-mediated synapse on cortical pyramidal neurones. However, in the majority of neurones, these putative transmitters activated other receptor types preferentially. The possibility that this may result from the greater accessibility of non-N-methylaspartate receptors to electrophoretically applied agonists, is discussed.