1. Phosphoinositide hydrolysis-linked excitatory amino acid (EAA) receptors (ACPD receptors) are selectively activated by the glutamate analogue trans-1-amino-1,3-cyclopentanedicarboxylic acid (trans-ACPD). Regional analysis of trans-ACPD-induced phosphoinositide hydrolysis indicates that this response is greater in the hippocampus than in other brain regions. Therefore we designed a series of studies aimed at testing the hypothesis that activation of this receptor modulates synaptic function in the hippocampal region. 2. We report that trans-ACPD dramatically altered field population spikes at each of the three major synapses in the hippocampal trisynaptic circuit at concentrations that are effective in activating phosphoinositide hydrolysis. At the perforant path-dentate gyrus synapse, bath application of trans-ACPD resulted in a decrease in the amplitude of field population spikes. In contrast, trans-ACPD markedly enhanced field population spike amplitude at the mossy fiber-CA3 synapse and the Schaffer collateral-CA1 synapse. In area CA 1, but not area CA3, trans-ACPD also induced generation of multiple population spikes. 3. Simultaneous field potential recordings from the s. pyramidale and s. radiatum in area CA1 revealed that the effect of trans-ACPD on population spikes in this region was not accompanied by an increase in the initial slope of the field EPSP. This suggests that the effect of trans-ACPD was not mediated by a presynaptic action but must be mediated by direct effects on CA1 pyramidal cells or by a decrease in synaptic inhibition. 4. trans-ACPD had a number of direct excitatory effects on CAl pyramidal cells. These included 1) cell depolarization (with an increase in input resistance), 2) inhibition of the slow after hyperpolarization, and 3) blockade of spike frequency adaptation. trans-ACPD also had effects on CA1 pyramidal cells that were not excitatory in nature. These included an increase in the threshold for initiation of calcium spikes and an increase in interspike interval during prolonged current injection. None of these effects were mimicked by an ACPD analogue that does not activate the ACPD receptor (trans-methanoglutamate), nor were they blocked by kynurenate, a nonselective EAA receptor antagonist that does not block the ACPD receptor. These data are consistent with the hypothesis that these effects are mediated by ACPD receptor activation. 5. In addition to its direct effects on CA1 pyramidal cells, trans-ACPD also indirectly enhanced excitatory synaptic responses in these cells by partially blocking synaptic inhibition. This was seen as an ACPD-induced decrease in paired-pulse inhibition and an ACPD-induced reduction of both the fast and slow components of evoked inhibitory postsynaptic potentials measured in CA1 pyramidal cells. 6. These data suggest that trans-ACPD alters excitatory synaptic responses at each of the three synapses in the trisynaptic hippocampal circuit. At the Schaffer collateral CA1 synapse, trans-ACPD markedly enhances excitatory synaptic responses by exerting direct excitatory effects on CA1 pyramidal cells and by decreasing synaptic inhibition.
