Neurophysiology: Dust Clearing on the Long-Term
Potentiation Debate
Convergence Emerges on LTP mechanisms - well almost
By Karen Heyman, The Scientist
Three decades and 6,000
papers since the term was first coined, scientists are still debating the
mechanisms of long-term potentiation (LTP).1 Defined in 1973 as an increase in
synaptic strength following experimentally induced high-frequency stimulation,2
LTP has been consistently controversial. Now at last, "There is a
consensus beginning to emerge," says Columbia University Nobel laureate,
Eric Kandel, as years of research have begun to make sense of what once seemed
irreconcilable contradictions. An almost decade-long argument over whether LTP
should be considered presynaptic or postsynaptic now appears settled, allowing
researchers to pursue finer details.
Among neuroscientists, the
"LTP equals learning" definition has given way to a broader
understanding of the process as a family of brain mechanisms involved in
associating stimuli. "I'm of the camp, and I've changed a lot over the
years, that LTP and LTD [long-term depression, the downregulated counterpart]
are basically core mechanisms, almost as fundamental as synaptic transmission
itself," says Robert Malenka of
Kandel, Malenka, and many
researchers now agree on the likelihood of several forms of LTP, mediated by
different biochemical subtleties. "All the mechanisms look superficially
the same, because they all make the synapse stronger," says Kandel, "but
they use somewhat different mechanisms. Some are completely postsynaptic,
some have in addition a presynaptic component. We now realize that different
forms of this family of synaptic plasticities are likely to map onto different
aspects of behavior."
The major problem behind
trying to get consensus is that researchers work in different parts of the
brain, including amygdala, hippocampus, and several areas of cortex, as well as
in the brains of invertebrates. LTP also uses different mechanisms at different
times of development.
Detecting Coincidence
Much current research is
focused on NMDA-dependent LTP in the CA1 region of the hippocampus. Excitatory
synaptic transmission depends on ionotropic receptors, primarily AMPA receptors
(AMPARs) and NMDA receptors (NMDARs), which are triggered by transmitter
release. Glutamate binds to AMPA, opening up an ion channel and producing
postsynaptic depolarization.
When the cell is at rest, the
pores of NMDARs are blocked by positively charged magnesium ions. For these
voltage-dependent channels to open, two things have to happen almost
simultaneously: glutamate release from the synapse, and the depolarization of
the cell by other inputs (often back-propagating action potentials from their
own somas). Thus, NMDARs work as coincidence detectors, at the conjunction of
two different stimuli (postsynaptic depolarization and presynaptic glutamate
release). In short, the associative process starts at the most basic
biochemical level. Roger Nicoll of the
Once the magnesium block is
released, calcium ions move into the cell and activate kinases, most
prominently calcium/calmodulin-dependent protein kinase II (CaMKII), leading
through phosphorylation to AMPAR insertion into the postsynaptic membrane.
Nicoll warns, "Most people are on board with that scenario up to
activation of CaMKII. Then it's a total murky mess up to AMPAR insertion."
The focus of much current research, including his own,
is filling in that gap.
Malenka, Nicoll, and working
separately, Roberto Malinow of Cold Spring Harbor Laboratory, reinforced the
idea of NMDARs as an associative mechanism when they discovered so-called
silent synapses, which have NMDARs but no AMPARs. Normally, the glutamate from
cell A should make cell B depolarize, but here cell B (lacking AMPARs) does
not. It is only by repeated activation of A and B firing together (for example,
when B is activated by another pathway), that an ongoing association is made
between these cells. After the repeated synchronous firing of A and B, AMPARs
are finally recruited into B by Ca2+ influx through its NMDARs.
The idea is most easily
understood in a developmental example: A baby's brain does not yet know how to
"wire up" the world. It needs to wait for repetitive associations of stimuli.
A silent synapse will eventually, through the process of LTP, get AMPAR
inserted. But the elegance of that solution belies how the original question
split the field in two: those who saw LTP as either presynaptic or
postsynaptic.
A Confounding Switch
Despite all the familiar
illustrations of synaptic clefts filled with neurotransmitter, it is actually
released infrequently. "Synapses release transmitter in a probabilistic
manner," says Nicoll, "and the probability is quite low." Typically
only one-fourth of activated presynaptic termini will release transmitters.
At the time of the pre- and
post- wars, the canonical idea was that if the synaptic failure rate went down,
then surely something had changed on the presynaptic side to increase the probability
of transmitter release. Then experiments uncovered synapses that confounded the
field: synapses that have NMDARs but no AMPARs. Yet when LTP was induced,
"You quickly got a full component of AMPA receptor current, without the
NMDA current changing at all," says Nicoll. That meant a decrease in
failure rate, but one that had to be postsynaptic in origin. If it were
presynaptic, then both receptors would have been affected.
Theories were advanced, many
of them focused on the idea that somehow something was going back to the
presynaptic side, " [These theories were] all incredibly 'Rube
Goldberg,"' says Nicoll, "The way everyone was tricked was that no
one had considered that you could just in an all-or-none manner turn on
synapses that were totally silent."
And so LTP was definitely
found to involve a postsynaptic change. Well, maybe. "There's an emerging
consensus that the Roger Nicoll view is correct. There's a postsynaptic
induction and postsynaptic expression under many forms of LTP in the hippocampus
in CA1. But with some forms produced at certain particular frequencies, there
also is a presynaptic contribution," says Kandel, "In CA3 [in the
hippocampus], there's consensus by almost everyone that it's almost certainly
presynaptic and it's PKA- [protein kinase A] mediated." In the fine
distinctions of the field, however, "almost" is an important
operator.
Learning Protocols
NMDARs have been observed in
invertebrates for more than 10 years; several labs have now reported NMDAR in
everything from hydra to squid. 3,4 Recently, Tim
Tully found that NMDARs mediate learning in Drosophila. 5 These discoveries
lend themselves to speculation about the ultimate role of NMDARs, says David
Glanzman of UCLA, "Maybe NMDA receptors evolved as the mechanisms of associative
learning ... or it could be that they evolved for something else and they were
'kidnapped' for learning. An animal has a mechanism whose essence is that it's
associative, and now it can use it to learn."
Whatever
their ultimate evolutionary origin, NMDARs appear to be an essential component
of the kind of associative learning familiar from Pavlovian classical
conditioning. In classical
conditioning, an unconditioned stimulus (US), to which an animal would
naturally react (e.g., a shock) is paired with a conditioned stimulus (CS) that
normally would not evoke a reaction (e.g., a tone, or in the case of the sea
slug Aplysia, a light touch).
Several experiments have
shown that monoamines such as serotonin and dopamine might possibly cause AMPAR
insertion, even without the activation of NMDARs. 6 Monoamines are also
essential to a form of nonassociative learning, called sensitization. In
sensitization, no pairing of stimuli occurs; the subject receives just one
negative stimulus several times over, sensitizing it to even mild forms of the
same stimulus. For example, an Aplysia that has had its tail shocked repeatedly
will become sensitive to mild touch.
Robert Froemke, a
postdoctoral researcher at UCSF with Christoph Schreiner and Michael Merzenich,
offers an interpretation that intrigues Nicoll as well: "I would argue
that why NMDA receptors are so critical is that they are association detectors.
Dumping on serotonin or dopamine is not associative; there's no A and B firing,
there's only A. With monoamines, A is telling B how to learn. With NMDAR, A and B are agreeing to learn something."
Pavlov Comes Of Age
One of the important
components of classical conditioning is timing: If the CS stimulus is presented
first, the sense of association between the two stimuli is strengthened. If the
The classic rule assumes an
oversimplified model, however, that provides no information about where the
cells are synapsing, or even whether location makes any difference. Now a new
generation of experimentalists with computational backgrounds has begun to look
at the where as well as the when of synaptic firing, in a new specialty called
spike timing-dependent plasticity (STDP). 7 "One of the reasons I believe
in STDP is when I look at the behavioral electrophysiology: How are spikes
produced in the animals running on tracks?" says Matt Wilson of the
Massachusetts Institute of Technology. "What you see is that the timing of
the spikes is produced in a way that preserves a lot of relative timing information."
In a recent paper, Froemke
and his graduate advisor, Yang Dan of UC-Berkeley, looked at the role of NMDARs
and STDP in a distal and proximal synapse in pyramidal neurons of rat visual
cortex. "Depending on where the synapse is in the dendrites, the timing requirements
are different. What that means is that different synapses have different rules
for learning," Froemke says.
In this scenario, the result
of the back-propagating action potential is that the NMDAR sees a short, tight
spike at the proximal dendrite. The distal dendrite has a much broader spike
that goes on for a much longer amount of time. The difference means a much
longer time window (on a millisecond scale) for coincidence detection the
farther a synapse is from the soma.
"People thought ... who
came first was key, and then the timing was key, and
the combination of those two explained everything. What this paper says is
there's another layer of complexity to all that, that it's not just order and
time. It's also about location," says Tom O'Dell of UCLA. "You can't
just say a synapse is a synapse in terms of plasticity; the rules that govern
whether or not you're going to get a change vary along the length of the
dendrite, which is amazing. It increases the computational power of the cell,
because the synapses on the dendrites are all so different."
In a provocative
interpretation, Froemke speculates that the results could also suggest that
"NMDA receptors may be much more active, much more highly tuned, [and]
extremely sensitive to small perturbations in synaptic transmission than
previously thought." But he admits this is far removed from anything they
showed in their paper. Froemke works in visual cortex, where NMDARs can
naturally be much more dynamic, says Nicoll, illustrating once again the
challenge of consensus in a field in which everyone works on the same process
but in different areas. Indeed, some researchers consider STDP to be possibly
the result of a change in induction protocols.
Kandel says that if one
changes the frequencies of stimulation during a plasticity protocol,
or the pattern of stimulation during a learning protocol, a set of different
mechanisms will likely be recruited to a different form of learning. Kandel
says: "We have gone through a complicated period. We now understand why
some of these differences existed between groups, because they were using
somewhat different protocols, and now we can begin to see which of these forms
of LTP map onto different forms of learning." As per usual, not everyone
agrees with this assessment of protocol disparity.
Perhaps
the only thing everyone does agree on is that LTP remains enormously
complicated. During the pre- versus post- debate, a theory called retrograde
transmission suggested that nitric oxide might be a neurotransmitter involved
in LTP. While Kandel says nitric oxide is still a "candidate
molecule" for LTP-induced presynaptic transmission, Malenka and others say
the theory's day has passed. When asked what he thought of the idea, Louis
Ignarro, winner of the 1998 Nobel Prize for his joint discovery of nitric oxide
as a signaling molecule in the cardiovascular system, deferred to the
neuroscientists: "It's hard to work on the brain. I would never work in
that area."
References
1. RC Malenka, MF Bear "LTP and LTD: an embarrassment
of riches," Neuron, 44: 5-21, 2004.
2. TVP Bliss "A journey from neocortex to
hippocampus," Phil Trans R Soc Lond B 358: 621-2, 2003.
3. N Dale, ER Kandel "L-glutamate may be
the fast excitatory transmitter of Aplysia sensory neurons," Proc Natl
Acad Sci, 90: 7163-7, 1993.
4. AC Roberts, DL Glanzman "Learning in Aplysia : looking at synaptic plasticity from both
sides," Trends Neurosci, 26: 662-70, 2003.
5. S Xia et al, "NMDA receptors mediate
olfactory learning and memory in Drosophila," Curr Biol, 15:603-15, April
12, 2005.
6. WB Smith et al, "Dopaminergic
stimulation of local protein synthesis enhances surface expression of GluR1 and
synaptic transmission in hippocampal neurons," Neuron, 45:765-79, March 3,
2005.
7. Y Dan, MM Poo "Spike timing-dependent
plasticity of neural circuits," Neuron, 44:23-30, 2004.
8. RC Froemke et al,
"Spike-timing-dependent synaptic plasticity depends on dendritic
location," Nature, 434:221-5. March 10, 2005.
Reprinted
with permission from The
Scientist. ©2005. Published in May 23, 2005 issue of The Scientist
(19(10):14-18).
Submitted: 08/24/05
This text was obtained from
the link:
http://professionals.epilepsy.com/page/ar_1124885128.html
(2011-04-24)
Figures in the original
publication in “The Scientist” are missing.