Downloaded from learnmem.cshlp.org on October 4, 2021 - Published by Cold Spring Harbor Laboratory Press REVIEW A Biochemist's View of Long-term Potentiation Erik D. Roberson, Joey D. English, and J. David Sweatt ~ Division of Neur0science Bayl0r College of Medicine Houston, Texas 77030 Abstract teractions. Explanations of LTP in terms of changes in synaptic structure (Edwards 1995) or on the This review surveys the molecular basis of silent synapses becoming functional (Isaac mechanisms of long-term potentiation et al. 1995) recently have been proposed. It is (LTP) from the point of view of a worth keeping in mind, though, that even those biochemist. On the basis of available data, processes must have some underlying biochemical LTP in area CA1 of the hippocampus is basis, for any persisting change in a neuron's func- divided into three phases--initial, early, and tion must be produced by a persisting change in late---and the mechanisms contributing to one or more of its proteins [or, perhaps less likely, the induction and expression of each phase in persisting changes to one of its two other mac- are examined. We focus on evidence for the romolecular complexes, DNA and RNA (see Crick involvement of various second messengers 1984)]. Thus, an explanation of LTP in terms of and their effectors as well as the biochemical changes is not mutually exclusive of biochemical strategies employed in each an explanation based on, for example, structure; in phase to convert a transient signal into a fact, a biochemical explanation is a necessary part lasting change in the neuron. We also of any complete structural explanation. consider, from a biochemical perspective, LTP can be induced in many different synaptic the implications of a multiphase model for pathways by a variety of induction paradigms, and LTP. the biochemical mechanisms of these forms of LTP may differ (e.g., Powell et al. 1994). We focus on the form of LTP whose biochemistry has been studied most extensively: N-methyl-n-aspartate Introduction (NMDA) receptor-dependent LTP induced by A simple way to think about the concept of multiple, 1-sec, l O0-Hz tetani at the Schaffer col- memory is as the creation of apersistent change in lateral pathway synapses in area CA1 of the hip- the brain by a transient stimulus, such as a thought pocampus. We begin by considering briefly the or experience. Long-term potentiation (LTP) is transient biochemical signal for LTP induction, a just this sort of phenomenon: A 1-see stimulus de- rise in intracellular calcium. Next, we review cur- livered to a group of presynaptic axons causes an rent progress in the pursuit of mechanisms that increase in the strength of their connections with underlie the prolonged effect of this brief signal on postsynaptic neurons that lasts for hours, weeks, synaptic transmission. It appears that LTP is pro- or months (Fig. 1A). By virtue of this and other duced by a series of distinguishable mechanisms properties, LTP has become a memory model stud- (Fig. 1B). Thus, our overview of LTP is based on a ied by researchers in many disciplines, from phys- contemporary model (Fig. 2) that dividesLTP into iology to molecular biology and from structural three distinct phases: (1) initial LTP (I-LTP), in- biology to behavioral psychology. This review ex- sensitive to most kinase inhibitors; (2) early LTP amines the mechanisms of LTP from our perspec- (E-LTP), subserved by the second-messenger inde- tive as biochemists. pendent activity of protein kinases, in particular We focus on individual proteins and their in- protein kinase C, calcium/calmodulin-dependent protein kinase II, and perhaps others; and (3) late LTP (L-LTP), distinguished from earlier phases ~Corresponding author. based on its dependence on protein synthesis. LEARNING & MEMORY 3:1-24 9 1996 by Cold Spring Harbor Laboratory Press ISSN 1072-0502/96 $5.00 L E A R N / N G & M E M O R Y I Downloaded from learnmem.cshlp.org on October 4, 2021 - Published by Cold Spring Harbor Laboratory Press Roberson et aL washed out. Expression mechanisms, on the other hand, are the processes brought about by the in- duction mechanisms that support synaptic poten- tiation directly. They are distinguished from in- duction mechanisms because inhibition of expres- sion mechanisms after the inducing stimulus causes established LTP to be diminished. Note that when the inhibitor is applied before the inducing stimulus and remains present throughout the ex- periment, or in a knockout experiment, it is im- possible to distinguish between effects on induc- tion and expression. Much more is known about the biochemical cascades that support induction mechanisms. Relatively little is known about ex- pression mechanisms, especially in I-LTP and L-LTP. We will provide a considerable discussion, though, of the expression mechanisms of E-LTP, where there is substantial evidence of a role for protein kinases. Figure 1: (A) Data from a typical LTP experiment. The In the model, the increase in intracellular cal- slope of the excitatory postsynaptic potential (EPSP), a cium during LTP initiation triggers the induction measure of synaptic strength, is measured over time with mechanisms of each of the three phases. After dif- an extracellular recording electrode. A steady baseline is fering delays, each of these induction mechanisms observed in response to constant-intensity stimulation of culminates in the expression of enhanced synaptic a group of presynaptic fibers. At the times indicated by efficacy and thus provides a component of LTP. the arrows, a series of 1-sec stimuli are delivered at 100 Conceptually, then, the potentiation observed dur- Hz. This brief stimulus produces a potentiation of the ing LTP may be divided and attributed to the three size of the EPSP which lasts for many hours. This figure illustrates two features of LTP: (1) the persistence of the expression mechanisms (Fig. 1B). effect following very brief stimuli, and (2) the stability, i.e., the constant magnitude of potentiation, over pre- sumed transitions between phases of LTP. (B) Schematic diagram of the data from A illustrating the phases of LTP. The potentiation observed in the experiment from A is fit by a LOWESS curve. The various phases of LTP are rep- resented by different shading: PTP, stippled; I-LTP, white; E-LTP, crosshatched; L-LTP, black. Note that suc- ceeding phases overlap, but that during transitions, the observed potentiation remains constant. The duration of each phase is approximate, based on available data (see text). We distinguish between two types of LTP mechanisms: induction and expression mecha- nisms. Conceptually, induction mechanisms are Figure 2: Schematic diagram of the various mecha- defined as the biochemical initial events set into nisms underlying LTP. Calcium influx is the apparent trigger of each phase of LTP, but initiates different mech- motion to lay the groundwork for a given phase of anisms leading to the various phases. Each phase of LTP LTP. These mechanisms are "silent" with respect comprises an induction mechanism (arrow), which does to synaptic transmission; they do not affect it di- not contribute directly to potentiation of the EPSP, but rectly but rather serve to consolidate the subse- serves to consolidate the expression mechanism (box), quent expression mechanism. Induction mecha- which does. Note the temporal overlap between multi- nisms are defined as those processes whose inhi- ple induction and expression mechanisms; for clarity, bition blocks LTP when the inhibitor is applied these mechanisms are represented as independent, but only during the inducing stimulus and then interactions between mechanisms are likely. L E A R N I N G & M E M 0 R Y Z Downloaded from learnmem.cshlp.org on October 4, 2021 - Published by Cold Spring Harbor Laboratory Press A BIOCHEMIST'S VIEW OF LTP For clarity, the phases are represented as com- tremely brief period of time during which calcium pletely independent in Figure 2. The extent to must set in motion numerous, long-lasting bio- which this is true and the means by which the chemical changes at the synapse. three phases may interrelate is discussed below. The Transient Signal CALCIUM SOURCES We begin by considering the nature of the There are two potential sources of the cal- transient signal. From a biochemical point of view, cium trigger for LTP: extracellular calcium influx a brief rise in postsynaptic intracellular calcium and calcium release from intracellular stores. In- above some threshold level serves as the trigger flux of extracellular calcium is mediated by at least for LTP. There is a variety of evidence to support two classes of transmembrane ion channels: the this, including the fact that calcium chelators in- NMDA subtype of glutamate receptor and voltage- jected postsynaptically can prevent the induction gated calcium channels (VGCCs). of LTP (Lynch et al. 1983), and that photolytic NMDA receptors contribute little to normal release of calcium from cage compounds in the synaptic transmission because of a voltage-depen- postsynaptic cell can trigger a long-lasting poten- dent magnesium block; the depolarization that oc- tiation like LTP (Malenka et al. 1988). Wc focus on curs during high-frequency stimulation relieves where and when calcium levels increase and on this block, and, with glutamate present at the ac- what constraints this signal might place on mech- tive synapse, calcium influx via activated NMDA anisms for LTP, with the goal of understanding the receptors occurs. NMDA receptor activation is re- mechanisms induced by the calcium trigger. quired for LTP induction, as LTP is blocked by a variety of NMDA receptor antagonists acting at various sites on the receptor. These include the competitive antagonist 2-amino-5-phosphonopen- CALCIUM IMAGING tanoic acid (APV) (Collingridge et al. 1983; Harris Imaging studies with calcium-sensitive dyes et al.