Matthies Learning and Memory

Mechanisms of Information Storage in the Nervous System
1. Auflage 2013
ISBN: 978-1-4831-6131-0
Verlag: Elsevier Science & Techn.
Format: EPUB
Kopierschutz: 6 - ePub Watermark

E-Book, Englisch, 428 Seiten

Learning and Memory: Mechanisms of Information Storage in the Nervous System contains the proceedings of the Seventh International Neurobiological Symposium held at Magdeburg on October 28 to November 2, 1985. Organized into four sections, this book first elucidates the synaptic long-term potentiation. Section II explores hippocampal functions, and Section III describes the biochemistry of memory formation. The last section addresses the principles and modification of learning behavior.

Autoren/Hrsg.

Matthies, Hansjurgen

Leseproben

Presynaptic Mechanisms in Hippocampal Long-term Potentiation

T.V.P. Bliss, M.L. Errington, K.J. Feasey and M.A. Lynch,     Division of Neurophysiology and Neuropharmacology, National Institute for Medical Research, Mill Hill, London NW7 1AA, UK

Publisher Summary

Although the long-term potentiation (LTP) of synaptic efficacy in the hippocampus following brief tetanic stimulation was first described in 1973, the mechanism underlying the phenomenon remains obscure. Evidence to date suggests that both pre- and post-synaptic mechanisms are involved in the induction of LTP. This chapter analyzes presynaptic mechanisms in hippocampal LTP. There is evidence that presynaptic mechanisms leading to a sustained increase in transmitter release are involved in the maintenance of LTP. The use of a technique in which electrophysiological recording is combined with push-pull perfusion has allowed to collect perfusate and monitor evoked potentials simultaneously and has, thus, made it possible to correlate changes in transmitter release with changes in electrophysiological responses.

INTRODUCTION

Although long-term potentiation (LTP) of synaptic efficacy in the hippocampus following brief tetanic stimulation was first described in 1973 (Bliss and Lømo, 1973), the mechanism underlying the phenomenon remains obscure. Evidence to date suggests that both pre- and post-synaptic mechanisms are involved in the of LTP. The first direct evidence indicating postsynaptic involvement was provided by Lynch and his colleagues, who showed that intracellular injection of EGTA into CA1 pyramidal cells prevented the induction of LTP in the majority of cells tested (Lynch, Larson, Kelso, Barrionuevo and Schottler, 1983). Since EGTA presumably blocks LTP by chelating cytoplasmic Ca2+ this result also emphasizes the importance of Ca2+ in the induction of LTP. The intracellular injection of caesium chloride, which blocks K+ currents, has also been reported to prevent the induction of LTP in treated cells (Haas and Rose, 1984). More recent experiments have suggested that intense dendritic depolarization is a necessary, though not sufficient, condition for the induction of LTP. Thus, depolarisation of the postsynaptic cell, whether produced by passing current through an intracellular electrode (Wigström, Gustafsson, Huang and Abrahams, 1986), or by iontophoresis of glutamate onto dendrites (Andersen, Hvalby, Hu and Lacaille, personal communication; see Andersen, 1986), failed to cause LTP; on the other hand, in both cases, the conjunction of depolarization with low-frequency stimulation of afferent fibres did result in LTP. It therefore seems likely that the induction of LTP requires activation of both presynaptic and postsynaptic components.

The mechanisms involved in the maintenance of LTP have been studied to a lesser extent. A postsynaptic hypothesis was proposed in 1980 by Baudry and Lynch (1980a), who suggested that high-frequency stimulation led to an increase in the number of postsynaptic glutamate receptors. It was suggested that the postulated unmasking of these additional receptors could result from activation of a Ca2+-dependent protease, following Ca2+ influx during high-frequency activation (Baudry and Lynch 1980a; 1980b). These authors later reported that the number of glutamate receptors was increased in membrane fractions obtained from potentiated CA1 slices compared to controls (Lynch, Halpain and Baudry, 1982). However, two subsequent studies, one in CA1 (Sastry and Goh, 1984) and the other in the dentate gyrus (Lynch, Errington and Bliss, 1985a) have failed to confirm an overall increase in glutamate binding in potentiated tissue, though an increase, beyond the resolution of the binding assay, in one or other of the glutamate receptor subtypes remains a possibility. Morphological studies have also provided evidence of postsynaptic involvement. Thus it has been reported that tetanization results in an increase in the diameter of dendritic spines in the perforant path terminal zone (Fifkova and van Harreveld, 1977) and an increase in the number of shaft synapses in CA1 (Lee, Schottler, Oliver and Lynch, 1980; Chang and Greenough, 1984). Morphological changes accompanying LTP in the dentate gyrus have also been observed (Wenzel and Matthies, 1985). Evidence that LTP is accompanied by changes in transmitter release, first suggested by experiments of Skrede and Malthe-Sørenssen (1981), has come from a series of and studies in our laboratory which will be reviewed in this chapter (Dolphin, Errington and Bliss, 1982; Bliss, Douglas, Errington and Lynch, 1985, 1986; Feasey and Lynch, 1984; Feasey, Lynch and Bliss, 1986). We will argue that our results provide strong evidence that the maintenance of LTP is linked to a sustained increase in transmitter release.

LTP AND TRANSMITTER RELEASE: STUDIES.

Use of a technique in which electrophysiological recording is combined with push-pull perfusion has allowed us to collect perfusate and monitor evoked potentials simultaneously (Errington, Dolphin and Bliss, 1983), and has thus made it possible to correlate changes in transmitter release with changes in electrophysiological responses. Using this method, our first experiments demonstrated that LTP in the perforant path-granule cell synapses of the anaesthetized rat was accompanied by a prolonged increase in release of 3H glutamate newly synthesized from 3H glutamine (Dolphin, Errington and Bliss, 1982). We have recently extended these studies to investigate the release of endogenous amino acids in the dentate gyrus following induction of LTP (Bliss, Douglas, Errington and Lynch, 1985, 1986). The results of these experiments are summarized in Fig. 1. In control animals, release of both glutamate and aspartate decreased with time but following the high-frequency train given to induce LTP, release of glutamate was increased and release of both amino acids was significantly enhanced compared to control. There was no significant change in release of glutamine or glycine. In the case of glutamate the change persisted for at least three hours after the train (third hour not shown), and was more marked than the increase in release of aspartate which persisted for only two hours. The increase in transmitter release is correlated with LTP rather than with the high-frequency train itself, as we have shown in a number of ways. In the first place, in animals in which the high-frequency train failed, for unknown reasons, to produce LTP there was no increase in the release of 3H glutamate (Dolphin et al, 1982). Furthermore, when the induction of LTP was suppressed by delivery of a high-frequency train of stimuli to the commissural input immediately before the high-frequency train was delivered to the perforant path (Douglas, Goddard and Riives, 1982), the associated increase in release of endogenous glutamate and aspartate was also blocked (Bliss et al., 1986). Finally, blocking the induction of LTP by perfusion of the NMDA antagonist APV prevented any increase in endogenous transmitter release (Lynch, Errington and Bliss, 1985). Thus in the dentate gyrus there is a consistent correlation between LTP and a sustained increase in transmitter release, strongly implying the existence of a presynaptic component in the maintenance of LTP.

Fig. 1 release of endogenous aspartate (Asp), glutamate (Glu), glutamine (Gln), and glycine (Gly) associated with stimulus-induced LTP in the dentate gyrus of rats anaesthetized with urethane. A push-pull cannula with attached recording electrodes was lowered into the molecular layer of the dentate gyrus, and the area perfused at a rate of 6 µL/min. Test shocks were delivered at 30 second intervals to the perforant path to monitor the amplitude of evoked population responses. Samples of perfusate were collected at 15 minute intervals. After 1 hour (arrows) animals in the experimental group received a single high-frequency train (250 Hz, 200 msec) to induce LTP. Fluorescent derivatives of amino acids were formed by mixing samples of perfusate with ophthalaldehyde/mercaptoethanol. Amino acids were separated by reverse phase HPLC, and quantified fluorometrically. Results are presented above as the mean hourly release (± SEM) of the four amino acids, expressed as a percentage of the mean in the first hour. In control animals (hatched histograms, n=8) release of all amino acids decreased with time. In experimental animals (plain histograms, n=8), release of aspartate and glutamate were greater than corresponding control values following the induction of LTP while Gln and Gly were unchanged. The increase was significant (p = 0.05) for two hours in the case of aspartate and three hours in the case of glutamate (third hour not shown). See Bliss et al (1986) for further details.

It is important to establish whether this association is a general phenomenon or confined to LTP in the dentate gyrus. In order to investigate this question, LTP was induced in area CA3 of the hippocampus by delivering a high frequency train to the excitatory commissural projection to pyramidal cells. Figure 2b shows that following the induction of LTP, there was a significant increase in...