Long-term potentiation of synaptic transmission in the hippocampus is the primary experimental model for investigating the synaptic basis of learning and memory in vertebrates. The best understood form of long-term potentiation is induced by the activation of the N-methyl-D-aspartate receptor complex. This subtype of glutamate receptor endows long-term potentiation with Hebbian characteristics, and allows electrical events at the postsynaptic membrane to be transduced into chemical signals which, in turn, are thought to activate both pre- and postsynaptic mechanisms to generate a persistent increase in synaptic strength.

A synaptic model of memory: long-term potentiation in the hippocampus

The discovery that mammalian cells generate nitric oxide, a gas previously considered to be merely an atmospheric pollutant, is providing important information about many biologic processes. Nitric oxide is synthesized from the amino acid L-arginine by a family of enzymes, the nitric oxide synthases, through a hitherto unrecognized metabolic route -- namely, the L-arginine-nitric oxide pathway1–8. The synthesis of nitric oxide by vascular endothelium is responsible for the vasodilator tone that is essential for the regulation of blood pressure. In the central nervous system nitric oxide is a neurotransmitter that underpins several functions, including the formation of memory. . . .

The L-Arginine-Nitric Oxide Pathway

Damage to the hippocampal system disrupts recent memory but leaves remote memory intact. The account presented here suggests that memories are first stored via synaptic changes in the hippocampal system, that these changes support reinstatement of recent memories in the neocortex, that neocortical synapses change a little on each reinstatement, and that remote memory is based on accumulated neocortical changes. Models that learn via changes to connections help explain this organization. These models discover the structure in ensembles of items if learning of each item is gradual and interleaved with learning about other items. This suggests that the neocortex learns slowly to discover the structure in ensembles of experiences. The hippocampal system permits rapid learning of new items without disrupting this structure, and reinstatement of new memories interleaves them with others to integrate them into structured neocortical memory systems.

Why there are complementary learning systems in the hippocampus and neocortex: insights from the successes and failures of connectionist models of learning and memory.

Recent work has shown that the hippocampus contains a class of receptors for the excitatory amino acid glutamate that are activated by N-methyl-D-aspartate (NMDA) and that exhibit a peculiar dependency on membrane voltage in becoming active only on depolarization. Blockade of these sites with the drug aminophosphonovaleric acid (AP5) does not detectably affect synaptic transmission in the hippocampus, but prevents the induction of hippocampal long-term potentiation (LTP) following brief high-frequency stimulation. We now report that chronic intraventricular infusion of D,L-AP5 causes a selective impairment of place learning, which is highly sensitive to hippocampal damage, without affecting visual discrimination learning, which is not. The L-isomer of AP5 did not produce behavioural effects. AP5 treatment also suppressed LTP in vivo. These results suggest that NMDA receptors are involved in spatial learning, and add support to the hypothesis that LTP is involved in some, but not all, forms of learning.

Selective impairment of learning and blockade of long-term potentiation by an N -methyl-D-aspartate receptor antagonist, AP5

Theta Oscillations in the Hippocampus

1. The effects of excitatory amino acids and some antagonists applied by ionophoresis to stratum radiatum in the CA1 region of rat hippocampal slices were examined on the locally recorded field e.p.s.p. evoked by stimulation of the Schaffer collateral-commissural projection. 2. L-glutamate, L-aspartate and the more potent and selective excitatory amino acids quisqualate, kainate and N-methyl-DL-aspartate (NMA) depressed the e.p.s.p., presumably through depolarization and/or a change in membrane conductance. 3. The depression induced by kainate considerably outlasted the period of ejection whereas NMA depressions were rapidly reversible and were often followed by a potentiation of the e.p.s.p. In higher doses NMA also depressed the presynaptic fibre volley. The possible involvement of these effects in neurotoxicity and synaptic plasticity is raised. 4. The selective NMA antagonist, DL-2-amino-5-phosphonovalerate (APV) applied in doses which abolished responses to NMA, had no effect on the e.p.s.p. but prevented long term potentiation (l.t.p.) of synaptic transmission evoked by high frequency stimulation of the Schaffer collateral-commissural pathway. Other antagonists which had little or no effect on normal synaptic transmission included D-alpha-aminoadipate (DAA), the optical isomers of 2-amino-4-phosphonobutyrate (APB) and L-glutamate diethylester (GDEE). 5. In contrast, gamma-D-glutamylglycine (DGG), applied in amounts which affected quisqualate and kainate actions as well as those of NMA, was an effective synaptic antagonist whilst having no effect on the presynaptic fibre volley. 6. These results indicate that the synaptic receptor in the Schaffer collateral-commissural pathway may be of the kainate or quisqualate type. Although NMA receptors do not appear to be involved in normal synaptic transmission in this pathway they may play a role in synaptic plasticity. The interaction of L-glutamate and L-aspartate with these receptors is discussed.

Excitatory amino acids in synaptic transmission in the Schaffer collateral-commissural pathway of the rat hippocampus.

1. The effects of the ionophoretic application of a number of excitatory amino acids and antagonists to the dendrites of CA1 neurones of rat hippocampal slices maintained in vitro were examined. Cells were excited by N-methyl-DL-aspartate (NMA), kainate, quisqualate, L-aspartate and L-glutamate; NMA was unique in causing cells to fire in bursts of repetitive discharges in contrast to the sustained firing seen with the other compounds. 2. D-(-)-alpha-aminoadipate (DAA) and (+/-)-2-amino-5-phosphonovalerate (APV) were selective NMA antagonists, the latter appearing to be the more potent; in addition both compounds potentiated the responses to kainate and quisqualate. L-glutamate excitations were affected less by APV than were those of L-aspartate. The antagonist properties of APV appeared to reside with the D-(-)-isomer. 3. gamma-D-glutamylglycine (DGG) in low ionophoretic doses inhibited NMA-, kainate- and aspartate-induced cell firing but at higher doses the quisqualate and glutamate responses were also decreased. 4. Kainate and NMA responses were blocked by D-(-)-2-amino-4-phosphonobutyrate (D-APB) which also had some action against the excitatory effects of L-aspartate. L-APB had no antagonistic effects, but often produced potentiation of amino acid excitations or was itself an excitant. 5. The effects of NMA and those of kainate and quisqualate were blocked by (+/-)-cis-2,3-piperidine dicarboxylate (PDA), but this compound itself had a direct excitatory effect. L-glutamate diethylester (GDEE) did not show specific antagonism of any amino acid excitations. 6. DGG and APV did not affect ACh excitations and these selective antagonists should be of value in studying the involvement of the excitatory amino acids in synaptic transmission in the hippocampus. Because they are less potent and/or have complicating direct effects PDA, GDEE, D- and L-APB may be less useful in this regard.

The antagonism of amino acid-induced excitations of rat hippocampal CA1 neurones in vitro.

1. The relative potencies of a number of analogues of L-glutamate as excitants of thalamic neurones in the rat have been compared. The most powerful compounds were kainate, ibotenate and (+/-)cis-1-amino-1,3-dicarboxycyclopentane. The D- and L-isomers of glutamate and aspartate were also compared. Whereas D-glutamate is approximately one-half as active as the L-form, D-aspartate is more potent than L-aspartate. 2. Computer analysis has indicated that ibotenate and cis-1-amino-1,3-dicarboxy-cyclopentane have relatively fixed and similar C alpha-N, Comega-N and C alpha-Comega interatomic distances which can also be achieved by glutamate in certain conformations of the molecule, but not by aspartate. 3. Parallel examination of the antagonists glutamate diethylester and D-alpha-aminoadipate has shown that the former preferentially reduces L-glutamate effects while the latter blocks the actions of other amino acid excitants more readily than those of L-glutamate. 4. The evidence is consistent with the hypothesis that at least two populations of neuronal receptors for the excitatory amino acids exist.

https://physoc.onlinelibrary.wiley.com/doi/pdf/10.1113/jphysiol.1979.sp012605

The excitation of mammalian central neurones by amino acids

Kainic acid and the glutamate receptor

The endogenous amino acids glutamate and aspartate depolarize mammalian neurons to produce excitation, and the rigid glutamate analogue 1-amino-1,3-cyclopentanedicarboxylic acid also has this effect. This compound exists as two pairs of geometric isomers, and in the present study the absolute configuration of the four isomers is assigned. The known (+)-S and (-)-R isomers of 3-oxocyclopentanecarboxylic acid were used as the basis for the synthesis. The cis and trans amino acids were obtained by fractional crystallization. Spectral data, including optical rotation, circular dichroism, and 13C nuclear magnetic resonance, are presented. The compounds were evaluated as excitants by microiontophoretic ejection into the dendritic region of impaled CA1 pyramidal neurons of rat hippocampal slices. One isomer, cis-1R,3R, mimicked completely the actions elicited by N-methyl-D-aspartic acid; the other three isomers were alpha-kainic acid like.

H. McLennan

Papers

Excitatory amino acids in synaptic transmission in the Schaffer collateral-commissural pathway of the rat hippocampus.

The antagonism of amino acid-induced excitations of rat hippocampal CA1 neurones in vitro.

The excitation of mammalian central neurones by amino acids

Kainic acid and the glutamate receptor

Synthesis, resolution, and absolute configuration of the isomers of the neuronal excitant 1-amino-1,3-cyclopentanedicarboxylic acid.