Eric W. Harris

Long-term potentiation in the hippocampus involves activation of N-methyl-D-aspartate receptors

A series of omega-phosphono-alpha-carboxylic acids were tested as antagonists of excitatory amino acid depolarizations and long-term potentiation (LTP) in region CA1 of rat hippocampal slices. The 5- and 7-phosphono compounds (+/- AP5 and +/- AP7) blocked N-methyl-D-aspartate (NMDA) depolarizations and prevented the induction of LTP of the synaptic field potential and population spike components of the Schaffer collateral response. +/- AP5 and +/- AP7 did not reduce kainate or quisqualate depolarizations and did not affect unpotentiated synaptic response amplitude. +/- AP4, +/- AP6 and +/- AP8 did not block amino acid excitant responses or LTP. These results demonstrate that NMDA receptors present in hippocampal region CA1 are not necessary for normal synaptic transmission, but are involved in the initiation of long-term synaptic plasticity.

Long-term potentiation of guinea pig mossy fiber responses is not blocked by N-methyl d-aspartate antagonists

Receptors preferentially activated by the excitatory amino acid N-methyl-D-aspartate (NMDA) do not mediate synaptic transmission in the hippocampus but are involved in initiating long-term potentiation (LTP) in hippocampal region CA1. We have examined the role of NMDA receptors in LTP of the commissural/associational and mossy fiber pathways to region CA3 pyramidal neurons. In the commissural/associational pathway, NMDA receptor blockers did not reduce synaptic responses but reversibly blocked the induction of LTP. In contrast, NMDA receptor blockers had no effect on mossy fiber LTP. These results suggest that induction of commissural/associational LTP differs from mossy fiber LTP, although the mechanisms underlying expression of LTP along these pathways could be similar. Kynurenate and L-2-amino-4-phosphonobutyrate, which potently reduce mossy fiber responses, also did not block induction of mossy fiber LTP.

NMDA receptor activation and early olfactory learning.

Norway rat pups have an enhanced olfactory bulb response to odors which they have learned to prefer early in life. When N-methyl-D-aspartate receptors are blocked pharmacologically before olfactory preference training, both the behavioral preference and the enhanced olfactory bulb response to the learned odor are suppressed. These results implicate the activation of these receptors in the kind of neural and behavioral plasticity that normally occurs during development.

Action of 3-((±)-2-car☐ypiperazin-4-yl)-propyl-1-phosphonic aci (CPP): a new and highly potent antagonist of N-methyl-d-aspartate receptors in the hippocampus

A new compound, 3-((+/-)-2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP), has been evaluated as an excitatory amino acid receptor antagonist using electrophysiological assays and radioligand binding. In autoradiographic preparations, CPP reduces L-[3H]glutamate binding in regions of the hippocampus rich in N-methyl-D-aspartate (NMDA) receptors, but not in regions rich in kainate sites. In isolated membrane fraction preparations, CPP displaces L-[3H]glutamate binding to NMDA sites, but does not compete with the binding of selective kainate or quisqualate site ligands. CPP potently reduces depolarizations produced by application of NMDA but not depolarizations produced by quisqualate or kainate. Its order of potency against excitatory amino acid-induced responses in the hippocampus is NMDA greater than homocysteate greater than aspartate greater than glutamate greater than kainate greater than or equal to quisqualate. CPP has no effect on lateral perforant path responses or on inhibition of these responses by 2-amino-4-phosphonobutyrate. Finally, at doses that do not affect Schaffer collateral synaptic transmission, CPP reversibly blocks the induction of long-term potentiation of Schaffer synaptic responses. This new compound is, therefore, a highly selective brain NMDA receptor blocker, and the most potent such by nearly an order of magnitude.

Effects of synaptic antagonists on perforant path paired-pulse plasticity: differentiation of pre- and postsynaptic antagonism

The effects of different synaptic antagonists on paired-pulse plasticity of medial perforant path responses were studied in rat hippocampal slices. Baclofen reduces the response to activation of the perforant path, but does not have the same net effect on the first and second responses to paired stimulation: baclofen lessens the percent paired-pulse depression of medial perforant path responses. Furthermore, at doses that reduced the control medial perforant path response by half, paired-pulse plasticity changed from paired-pulse depression to paired-pulse potentiation. A similar effect on medial perforant path paired-pulse plasticity is produced by decreasing extracellular calcium concentration. Kynurenic acid reduces the first and second responses to paired stimulation proportionately the same, and, therefore, has no effect on the percent paired-pulse depression. These results suggest that baclofen acts presynaptically to reduce the synaptic response, whereas kynurenate acts postsynaptically. Adenosine was also found to be a potent antagonist of medial perforant path responses, with effects on paired-pulse plasticity similar to baclofen: a new synaptic antagonist, N-p-chlorobenzoyl-piperazine-2,3-dicarboxylate, was found to have effects like kynurenate, suggesting that it is also a postsynaptic receptor blocker.

Regulation of glutamate receptors: possible role of phosphatidylserine

The polar head group of the phospholipid phosphatidylserine is similar in structure to the glutamate analogue 2-amino-4-phosphonobutyric acid (APB), an antagonist of excitatory transmission in the brain. When tested in ligand binding assays phosphatidylserine and its polar head group components O-phosphoserine and L-alpha-glycerophosphoserine were good displacers of APB-sensitive L-glutamate binding. The polar head group components were also antagonists of synaptic field potentials in the rat dentate gyrus evoked by stimulation of a presumed glutamate-using pathway. These results suggest that phosphatidylserine may regulate the activity of synaptic L-glutamate receptors.

Structure-activity relationships of l-glutamate receptor ligands: Role of the ω-acidic terminal☆

Acidic amino acid analogues varying in their ω-terminal were evaluated: (1) as neuronal excitants or antagonists of excitatory synaptic transmission, and (2) as inhibitors of l-[3H]glutamate binding to synaptic membranes. ω-Phosphonates were antagonists and inhibited l-glutamate binding to the 2-amino-4-phosphonobutyrate (APB)-sensitive population of binding sites; ω-sulfonates and ω-carboxylates were excitants and inhibited l-glutamate binding to APB-sensitive and -insensitive sites. The data indicate that properties of the ω-acidic group are important for establishing the relative potencies of antagonist substances and the overall excitatory/antagonist activity of these analogues.