Published online 20 March 2003

Introduction

1. LONG-TERM POTENTIATION Gardner-Medwin 1973) using stimulation techniques that

triggered activity in hundreds, or perhaps thousands of
This issue of Philosophical Transactions celebrates the 30th
neurons. In Oslo, careful measurements of synaptic
anniversary of the first detailed description of long-term
responses recorded on film by a camera placed in front of
potentiation (LTP) in two papers published in 1973 in the
an oscilloscope screen provided a degree of quantitative
Journal of Physiology (Bliss & Lmo 1973; Bliss &
rigour; in London, an early laboratory computer was
Gardner-Medwin 1973). These two papers brought to a
pressed into service. Today, this approach (with film giv-
wider audience a phenomenon that had been discovered
ing way to the desktop computer) is pursued alongside
by Lmo a few years earlier, and published as an abstract
astonishing new technology, including multiphoton con-
in 1966 (Lmo 1966). In LTP, the strength of synapses
focal microscopy that allows, for example, the imaging of
between neurons in the central nervous system is
synaptic transmission at single synapses, or the passage of
potentiated for prolonged periods following brief but
receptor proteins to be monitored as they shuttle between
intense synaptic activation. Thirty years of research have
the cytosol and the synaptic membrane. However sophisti-
made this one of the most extensively studied topics in
cated the technique that is used to study it, the phenom-
contemporary neuroscience. Yet LTP continues to puzzle
enon itself, robust and abrupt, continues to fascinate. To
and intrigue us today, with many of the fundamental ques-
quote Bliss & Lynch (1988, p. 3): No matter how often
tions relating to the cellular mechanisms and functional
one has witnessed the phenomenon, it is impossible not
relevance of LTP remaining unanswered.
to retain a sense of amazement that such modest stimu-
What is the basis of this continuing interest? Our answer
lation can produce so immediate, so profound, and so per-
to this question and the reason for holding a Discussion
sistent an effect.
Meeting at The Royal Society is that LTP has, for neuro-
For most, the defining property of LTP is its persist-
scientists, turned into something of a treasure chest. Its
ence. Would there be as much interest in LTP if the long
exploration has led to all manner of findings, issues and
were replaced by shortif it only lasted for a few
further questions. We can justly claim that LTP has been
minutes? The simple truth is that there would not. Inside
enhancing neuroscience for 30 years.
our treasure chest is a neuronal magic wand whereby
Two themes have dominated research in this area. The
extremely brief patterns of electrical stimulation (such as
first key question is whether the neural mechanisms of
a short burst of high-frequency pulses) trigger biochemical
LTP are the same as, or at least overlap with, those
and structural changes that long outlast the stimulation.
responsible for learning and memory. Is it a neural model
This is a trick that the nervous system must perform if it
of memory formation, or is it the actual neural mechanism
is to make memories. And it is a trick that the nervous
that is used by the brain to store at least some forms of
system does perform to express LTP. The correspondence
acquired information? Second, and irrespective of the
teases the imagination.
answer to the first question, can we find out more about
However, persistence is only one of the treasures inside
how synapses work by studying the mechanisms by which
the chest. Other classical properties include input speci-
they change in strength? Synapses communicate, and they
ficity and associativity, and more recently identified
can do this either weakly or strongly. Their ability to
properties including metaplasticity, synaptic tagging and
change in strength is therefore a critical property that we
the converse phenomenon of long-term depression
must understand if we are to comprehend the nervous sys-
(LTD). Collectively, these are the kinds of properties that
tem. These two themes, one functional and the other
neural network engineers dream about when designing a
mechanistic, are fundamental to an understanding of how
biologically realistic system to emulate memory. The con-
the nervous system works, and researchers have under-
tributions in this issue describe and attempt to explain
standably been attracted to them as issues around which
these and many other properties, and their functional
to exercise their scientific imagination.
implications.
The 30 years of research since 1973 have seen major
developments in our conceptual understanding of activity-
dependent synaptic plasticity, not least because of spec- 2. STRUCTURE OF THE ISSUE
tacular developments in experimental techniques. In the
In creating and editing this special issue of Transactions,
experiments leading up to the 1973 papers, LTP was elic-
we had to be selective. It accompanies a Discussion Meet-
ited in the intact rabbit, initially in anaethetized animals
ing that is to be held on 29 and 30 May 2003 at The
at the University of Oslo (Bliss & Lmo 1973), and later
Royal Society, London, to which we have only been able
in awake animals at University College London (Bliss &
to invite a handful of speakers. Such is the effort going
into research on activity-dependent synaptic plasticity that
we could easily have held a much longer conference, but
One contribution of 30 to a Theme Issue Long-term potentiation: practicalities constrained us with respect to the aspects of
enhancing neuroscience for 30 years. synaptic plasticity that we could cover. The themes that

Phil. Trans. R. Soc. Lond. B (2003) 358, 607611 607 2003 The Royal Society
DOI 10.1098/rstb.2003.1282
608 T. V. P. Bliss and others Introduction
we eventually chose are (a) History, (b) Induction, (c)
Expression, (d) Persistence, (e) Function and (f) New direc-
tions. In extending invitations, we asked people who had
made original contributions to one or more of these topics,
but we did so in the uncomfortable knowledge that there
are many others whom, with equal justification, we might
have invited.
(a) History
How was LTP discovered? What happened? What hap-
pened next? And do the pioneers of the field agree about
these first steps? For every history, there is a pre-history
and Andersen (2003) takes readers back to one of the
classical ages of neurophysiologythe extraordinary 20-
year period from 1952 until around 1972. He emphasises
the contribution of Sir John Eccles, who well understood
that the primary issue was to demonstrate the existence of
synapses in which activity-dependent changes in efficacy
lasted for hours rather than minutes. In separate papers,
Lmo (2003) describes the serendipitous circumstances
that resulted in his discovery of LTP in 1966, and takes
us through the experiments with Bliss in 19681969 that
were eventually published in 1973. Bliss (2003) recalls
how frustration with the complexity of the neocortex led
him to the hippocampus, to Andersens laboratory, and
to the collaboration with Lmo. That the research they
describe was largely completed four years before it was
published is a reminder of a gentler age when matters were
pursued at a more leisurely and arguably more reflective
pace. Soon after the paper was published, Lmo left the
field to pursue a distinguished career in another branch of
neurophysiology. Blisss interests also diverged for a few
years, and it was Lynchs laboratory in California (Lynch
2003) and Andersens in Oslo, both using the new in vitro
hippocampal slice preparation, that were largely respon-
sible for sustaining and promoting interest in LTP. By the
late 1970s, LTP had begun to arouse interest worldwide.
A Caledonian link also came early, with pioneering
research on the properties and functions of LTP in the
intact animal conducted in Graham Goddards laboratory
in Nova Scotia, as summarized by McNaughton (2003).
Soon after, in 1983, came the discovery of the critical role
of the N-methyl-d-aspartate (NMDA) receptor in the
induction of LTP by Collingridge and colleagues at the
University of British Columbia (Collingridge 2003).
Around the same time, Morris developed the watermaze
in Scotland and conducted some of the early studies using
this task that have revealed the importance of hippocampal
LTP for spatial learning (Morris 2003).
There is much more to be written about the history of
LTP than we have space to cover here, but we hope that
these articles, written in a more personal style than is usual
in Philosophical Transactions, will give a flavour of the intel-
lectual climate in which the early advances were made.
(b) Induction
LTP is conventionally separated into two phases: induc-
tion and expression, with expression having several tem-
poral components. Not all synapses are the same. Some
show LTP, some do not; of those that do, many rely on
the NMDA receptor, but others do not. The biophysical
properties of the NMDA receptor, coupled with its regu-
lation by GABA receptor-mediated inhibition, explains
Phil. Trans. R. Soc. Lond. B (2003)
many of the defining characteristics of LTP where this
receptor is the trigger for induction, including associativity
and input-specificity. At other synapses, where induction
is independent of NMDA receptors, there is growing evi-
dence that another class of glutamate receptorthe kain-
ate receptorplays a pivotal part.
Synapses in which the induction of LTP is dependent
on the NMDA receptor, as well as those in which it is
not, can display activity-dependent LTD in synaptic effi-
cacy. LTD in the hippocampus is more easily elicited in
young animals and comes in two flavours. Once synapses
are potentiated, the level of synaptic efficacy can be
reversed by prolonged low-frequency stimulation in a pro-
cess known as depotentiation, as first noted by Lynch and
colleagues (Barrionuevo et al. 1980). In addition, it is also
possible to induce LTD in naive pathways (i.e. pathways
in which LTP has not been experimentally induced). This
type of LTD was first observed in the cerebellum by Ito &
Kano (1982), but is now also widely studied in the hippo-
campus, and is sometimes referred to as de novo LTD to
distinguish it from depotentiation. An important property
of hippocampal plasticity is its bidirectionality; the same
synapses can, according to circumstances, be potentiated,
depotentiated or depressed.
Finally, recent research has validated Hebbs notion
that the firing of the postsynaptic cell may be crucial for
whether or not LTP occurs (Hebb 1949). In the simplest
account of how neurons work, dendrites transduce
incoming activity into synaptic currents, the cell-soma
integrates these and generates an action potential once a
threshold is exceeded. Axons then transmit action poten-
tials away from the cell body, sometimes over long dis-
tances, to other neurons. Recent work has shattered the
simplicity of this polarized world, in which activity pro-
ceeds in one direction, from dendrite to soma to axon. It
is now known that action potentials can back-propagate
from the soma into the dendritic tree. The timing of these
back-propagating action potentials relative to the synaptic
input can play a critical part in determining the polarity
of synaptic change.
These subjects are covered in this issue by a set of three
papers. Bear (2003) discusses evidence supporting the
(Bienenstock et al. 1982) theory of the induction of bidi-
rectional plasticity as it applies to the visual cortex. Borto-
lotto et al. (2003) describe the very different mechanisms
of induction of potentiation at mossy fibre synapses in area
CA3 of the hippocampus. And Johnston et al. (2003)
transport us into the back-propagating world of spike-
timing-dependent plasticity.
(c) Expression
The next step, LTP having been induced, is to reveal
how the enhanced synaptic potentiation is expressed.
Here, it is necessary to approach the treasure chest with
care, for a veritable battleground is revealed within. In the
left corner stand the marshalled forces of the presynaptic
army. To make synapses stronger, they assert, it is only
necessary for the synapse to release more transmitter or,
at least, to release transmitter with a greater probability
when an action potential invades the presynaptic terminal.
That is what happens at axons of the neuromuscular junc-
tion, when one action potential rapidly follows another,
and also at central synapses; so perhaps similar, longer-

lasting mechanisms can also be pressed into service. In the
right corner, across the narrow synaptic cleft, stand the
battalions of the postsynaptic army. The NMDA receptor
is on the postsynaptic side of hippocampal glutamatergic
synapses, they proclaim. Since it is the locus of control
for the induction of the most prominent form of LTP,
why should LTP expression be any more complex than a
cascade of biochemical events inside postsynaptic den-
dritic spines whose net effect is to increase postsynaptic
receptor efficacy? Whereas the presynaptic forces acknowl-
edge the simplicity of an arrangement that assigns both
induction and expression mechanisms to the postsynaptic
side of the synapse, they claim that the necessary com-
munication between the two sides could be accomplished
by a retrograde messenger, signalling to the presynaptic
side that the conditions for the induction of LTP have
been met postsynaptically. The identity of the putative
retrograde messenger remains elusive. (In another theatre
of the campaign, a truce has been declared; most comba-
tants agree that presynaptic mechanisms contribute to the
expression of LTP at the mossy fibre pathway in the hip-
pocampus, which, incidentally, was the first non-NMDA
receptor-dependent form of LTP to be found; Harris &
Cotman 1986.)
The opposing armies have fought a long and tough-
minded trench war and their struggles have led to major
advances in our conceptual understanding of synaptic
function, new techniques and experimental protocols of
great beauty and elegance. Work in vivo was quickly sup-
plemented by the development of the in vitro brain slice,
allowing greater precision and control. Discoveries about
glutamate receptors came along, stimulated by the devel-
opment of new agonists and antagonists that were
deployed to reveal the relative contributions of NMDA
receptor-mediated and AMPA receptor-mediated currents
to LTP induction and expression. Creativity emerged in
paradoxical ways in laboratories around the world, as in
the analytical studies by which a postsynaptic channel-
blocking drug (MK-801) was deployed to monitor
changes in presynaptic transmitter release in short- and
long-term forms of potentiation. For theoretically exacting
studies, extracellular population recordings gave way to
paired-recording techniques between identified neurons
hard work but necessary workand more recently, several
groups have enthusiastically embraced the potential of
optical recording techniques to provide vivid and compel-
ling pictures of synaptic function at the level of the single
synapse. Conceptual developments are many and com-
plex, as the papers in this section reveal, and they have
also included a degree of lateral thinking about quantal
analysis and synaptic biophysics. One example was the
realization that a reduction in the number of transmission
failures, conventionally regarded as a presynaptic change,
might actually be postsynaptic in origin at central syn-
apses. As a result of the inside-out thinking about this and
related issues emerged the rediscovery of the concept of
the silent synapse. In contemporary guise, this is a syn-
apse at which transmitter is released, but that lacks AMPA
receptors on the postsynaptic membrane.
Bliss and his colleagues have long taken the view that
LTP has a presynaptic component. Errington et al. (2003)
summarize their earlier in vivo measurements of LTP-
associated increases in extracellular glutamate, and then
Phil. Trans. R. Soc. Lond. B (2003)
Introduction T. V. P. Bliss and others 609
describe results obtained with a new weapon in the pre-
synaptic armoury, the glutamate dialysis electrode, which
allows real-time estimates of glutamate concentration to
be made. Hosokawa et al. (2003) describe the use of
optical recording techniques to examine changes in net-
work behaviour following the induction of LTP in hippo-
campal slices, while Choi et al. (2003) discuss the concept
of fusion pore release in relation to glutamate transmitter
release and how this idea might help us to think about
silent synapses in a different way. Prominent among the
postsynaptic army, Malinow (2003) outlines the mech-
anisms by which AMPA receptors might be trafficked to
and from the receptor membrane, a process that he teas-
ingly describes as AMPAfication. Duprat et al. (2003)
follow up by discussing aspects of the relevant molecular
mechanisms, notably the binding of specific proteins to
the C-terminus of AMPA receptor subunits. Nicoll (2003)
summarizes a large body of data from his laboratory that
supports a postsynaptic view of LTP expression at
Schaffer commissural synapses on CA1 cells. Kullmann
(2003) provides a cautionary note. The first to introduce
the concept of the silent synapse into the debate about
the locus of the expression of LTP, he presents a cogent
argument that some pieces of the jigsaw puzzle remain to
be put in place.
(d ) Persistence
So far, the papers have described the ways in which syn-
aptic plasticity is induced and how it is expressed. How-
ever, the descriptions reveal that these processes are highly
dynamic. Ion fluxes through ligand- and voltage-gated
channels stimulate a rich and complex array of signal
transduction pathways and proteinprotein interactions,
including classical processes such as protein phosphoryl-
ation. Given that proteins turn over relatively rapidly, the
longevity of LTP presents us with an enormous puzzle.
How does the change persist?
For the present, we do not know the answer to this
question. Indeed, we do not even know how long LTP
itself can last. If it is to be accepted as a valid model of
memory, then the mechanisms responsible for the
expression of LTP must be capable of sustaining
enhanced synaptic strength for long periods, perhaps as
long as a lifetime. Abraham (2003) has long been inter-
ested in this enigma and by tweaking the induction para-
meters has found a set of conditions in which LTP can
be shown to last for at least a year in the rat. This is a
remarkable finding, although it does not establish that
LTP-like changes normally last as long as this. There may
also be important regional differences in the persistence
of LTP.
The other authors in this section discuss possible mech-
anisms and approaches by which the puzzle of persistence
could be tackled. Harris et al. (2003) describe anatomical
studies at the level of the light and electron microscope
that have revealed protein synthesis-dependent changes in
dendritic spines. Schuman & Murase (2003) make the
case for cadherins and local protein synthesis. E. R. Kan-
del has, throughout his long career, juggled his interest in
the hippocampus with his pioneering studies of an invert-
ebrate neural system, the abdominal ganglion of Aplysia.
His paper with Pittenger (Pittenger & Kandel 2003) puts
forward the argument that a route to learning more about
610 T. V. P. Bliss and others Introduction
the genetic mechanisms by which long-lasting synaptic
change may be regulated might best be approached in the
marine animal first. There are various reasons why the
apparently simpler range of, for example, transcriptional
controls, may make this preparation desirable for a first
analysis.
(e) Function
Most discussion of the possible functions of LTP has,
since its discovery, focused on the part that its underlying
mechanisms might play in laying down memory traces in
the brain. This is by no means its only possible function,
nor indeed should it be thought that there may not be
other mechanisms at the brains disposal for ensuring last-
ing changes as a consequence of neuronal activity. How-
ever, the synaptic plasticity and memory hypothesis has
been widely discussed.
One of the pioneers in the field was Barnes (2003) who
was among the first to establish that the temporal persist-
ence of LTP covaried with the persistence of memory.
Was this correlation an accident, or might it reflect a cau-
sal relationship? To establish such a possibility, it was
essential to find ways of blocking or enhancing LTP in
behaving animals and then investigating whether they
showed corresponding changes in their ability to learn cer-
tain tasks or to remember information once acquired. The
problem with doing such experiments is that LTP may
have different functional attributes when it occurs in dif-
ferent networks and circuits in the brain. That is, what
LTP does in the amygdala may be functionally different
from what it does in the hippocampus. Morris et al. (2003)
discuss this subject in the particular context of their
attempt to develop a neurobiological theory of the hippo-
campus in which LTP plays a part.
One of the exciting new developments of recent years
in neuroscience has been the marriage of techniques
across many different levels of analysis. This is particularly
clear in the use of transgenic animals in behavioural stud-
ies. A molecular intervention is madebe it the over-
expression or deletion of a geneand the consequences
of this intervention are examined at the highest level of
analysis, namely that of behaviour. S. Tonegawa was a
pioneer in this field and he and his colleagues describe his
recent development of regional-specific alterations of the
NMDA receptor and second-messenger transduction cas-
cades and their impact on LTP, learning and the behav-
iour of neural ensembles (Tonegawa et al. 2003). In a
similar vein, Hedou & Mansuy (2003) examine the conse-
quences of inducible inactivation of protein phosphatases
on LTP and behaviour, while Bozon et al. (2003) use
transgenic and more traditional techniques to examine the
relationship between gene expression, early and late LTP
and short- and long-term memory.
(f ) New directions
There may be a tendency for those outside the immedi-
ate field to suppose that research on LTP remains locked
within the hippocampus, the brain area in which it was
discovered. Not so. Part of what is exciting and invigorat-
ing about LTP is that the field is constantly expanding
into new areas. The final four papers in the issue highlight
examples of some new approaches. Thomas & Malenka
(2003) discuss activity-dependent changes in the striatum,
Phil. Trans. R. Soc. Lond. B (2003)
notably those induced by drugs of abuse that occlude the
subsequent induction of striatal LTP. Demonstrating
occlusion is a classic way of establishing commonality of
underlying mechanismsraising the intriguing and
important possibility that the neurobiology of LTP could
shed light on why drugs of abuse are so rewarding. Rowan
et al. (2003) take us into the domain of animal models of
Alzheimers disease and discuss a range of different
approachespharmacological and transgenicthat have
revealed striking alterations in fast synaptic transmission
and LTP in these models.
Finally, Lisman (2003) takes on the ambitious task of
attempting to tie things together. In his comprehensive
overview and synthesis of the molecular mechanisms
underlying the expression of LTP he finds room for both
presynaptic and postsynaptic components, bringing this
anniversary issue to a consensual and harmonious con-
clusion.
Tim V. P. Bliss1
Graham L. Collingridge2
Richard G. M. Morris3 January 2003
1
Division of Neurophysiology, National Institute for Medical
Research, Mill Hill, London NW7 1AA, UK
2
MRC Centre for Synaptic Plasticity, Department of Anat-
omy, School of Medical Sciences, University Walk, Bristol
BS8 1TD, UK
3
Centre and Division of Neuroscience, College of Medicine and
Veterinary Medicine, The University of Edinburgh, 1 George
Square, Edinburgh EH8 9JZ UK
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