This study examined the relationship between the affinity of glutamate agonists for the a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors and the characteristics of the physiological responses elicited by endogenous activation of the AMPA receptors. We tested the effects of chaotropic ions on [3H]AMPA binding in synaptic membranes as well as on synaptic responses elicited in CAl by electrical stimulation of the Schaffer/commissural pathway in the in vitro hippocampal slice preparation. Of the chaotropic ions tested, only perchlorate and thiocyanate produced large A number of experimental manipulations modifies the binding properties of the a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) subtype of glutamate receptors. In particular, treatment of synaptic membranes with phospholipases (C and A2) (1, 2), with reagents acting on SH groups (3), and with phosphatidylserine (4) increases the affinity of AMPA receptors for agonists. Similarly, AMPA binding is increased in hippocampus by high-frequency stimulation of the perforant path (5) and by classical conditioning (6). Electrophysiological studies of the long-term potentiation (LTP) of synaptic transmission that follows brief bursts of high-frequency electrical stimulation in various excitatory pathways (7) indicate that the increase in synaptic efficacy is due, at least in part, to a change in the component of synaptic responses mediated by AMPA receptors (8-10). These, and other findings, led us to propose that LTP is due to a modification of postsynaptic structures that includes a selective modification of the AMPA receptor, in a way that increases its responsiveness to the neurotransmitter (11, 12). Attempts to integrate the two sets of data (i.e., the biochemical and the physiological data) raise the obvious question of the relationship between the binding affinity of the agonists for the receptor and the characteristics of the physiological response elicited by the agonists. Although this has been addressed for many different receptors (13, 14), there are no general rules describing the nature of the relationship.We investigated this question by taking advantage ofseveral tools available for the study of glutamatergic transmission. (i) The hippocampal slice preparation provides a convenient way to assess global parameters of glutamate receptor responses; under normal ionic conditions, the excitatory postsynaptic potential (EPSP) recorded in the CA1 dendritic field is due almost entirely to the activation of AMPA receptors, whereas in the presence of low Mg2+ concentrations and 6,7-dinitroquinoxaline-2,3-dione (DNQX), a selective AMPA receptor antagonist, N-methyl-D-aspartate (NMDA) receptormediated currents are the major contributors to the EPSP (9,15 Abbreviations: AMPA, a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; CNQX, 6-cyano-7-nitroquinoxaline-2,3-dione; DNQX, 6,7-dinitroquinoxaline-2,3-dione; NMDA, N-methyl-Daspartate; LTP, long-term potentiation; EPSP, excitatory postsynaptic potential; TBS, theta burst ...