Oslo,
1964. A malaise had settled over the community of
neurobiologists investigating the biological substrates of memory. Obviously, memories can last for the
lifetime of an animal. Thus it was
expected that experience should produce long-lasting changes in neuronal
function to underlie the memory trace.
The best guess for the aspect of neuronal function changed by experience
was synaptic transmission.
Synaptic transmission is the fundamental mode of rapid communication
between neurons and so is central to information processing in the brain. The
dominant hypothesis was that particular patterns of neuronal stimulation
delivered to neurons with electrodes (thereby mimicking actual experience in
the world) would produce long-lasting changes in the strength of synaptic
transmission. The problem at the
root of the malaise: no evidence
whatsoever for this postulated mechanism. The longest-lasting changes that had been recorded
persisted for only a minute or two— a time scale that was totally insufficient
for memory storage.
In 1964, Terje
Lomo was a doctor in the Norwegian navy, soon to be discharged. On leave in Oslo to look for a job, he
bumped into the neurophysiologist Per Andersen, walking down the street. After an animated conversation about
synapses and neurons, he agreed to join Andersen’s laboratory as a Ph.D.
student. At that time, recordings
of synaptic function in the brain were, for a variety of technical reasons,
very difficult. Most recordings of
neuron-to-neuron synapses had been performed in the spinal cord (these yielded
the aforementioned brief facilitation).
Andersen had developed techniques to record synaptic transmission in a
brain region called the hippocampus, buried deep within the temporal lobe of
anesthetized rabbits. Lomo took up
these techniques and began to probe the properties of hippocampal
synapses. In 1965, he had the
first hints that repeated stimulation (120 pulses at 12 pulses/second), could
cause synapses to persistently increase their strength. However, it was not until the Fall of
1968, when Lomo was joined by Tim Bliss, a visiting British scientist with an
interest in memory storage, that things really took off. In their first experiment together they
used a design in which a single test pulse was delivered to measure the
synaptic strength. After recording
a series of stable baseline responses, a “conditioning stimulus” consisting of
300 pulses at 20 pulses/second was delivered. Following
several repetitions of this conditioning stimulus, the response to the
test pulse was larger, reflecting an increase in synaptic strength. Most importantly, this increase
persisted, not for a minute or two, but for many hours—as long as the recording
could be maintained. That day in
1968 marked the first real glimpse of a memory storage mechanism in the brain
and began the modern era of memory research, in which memory is analyzed at a
cellular and molecular level.
Lomo and Bliss
called their new phenomenon long-lasting potentiation or LLP. However, as often happens in science,
this name didn't stick, and it is now known as long-term synaptic potentiation
or LTP (Bliss once remarked that the expression “LLP” didn't catch on because
it made the speaker sound as if he were in need of urgent assistance). Starting in 1970’s, LTP created
tremendous excitement among memory researchers not only because of its
duration, but also because of it relation to a well-known neurological
case.
H.M. was a patient who underwent surgery to control otherwise intractable epilepsy. The surgery, which involved bilateral resection of his hippocampus and some surrounding tissue, cured the epilepsy, but left him with two profound memory impairments: he could no longer recall facts and events for a period of 1 – 2 years prior to the surgery, and, even stranger, he could no longer form any new memories for facts and events. Thus, the hippocampus was already implicated in memory storage. At that time, the idea was that LTP (and its later-discovered mirror twin, long-term synaptic depression or LTD) were rare phenomena, that would only be found at a few specialized synapses in the brain with particular roles in memory storage. That has not turned out to be the case at all: LTP and LTD are nearly ubiquitous properties of synapses and can be found everywhere from the spinal cord to the most recently evolved portions of the frontal cortex, and almost every brain region in between. Even the most ancient parts of our brain, that we share with fish and lizards, regions that control basic functions like spinal reflexes, breathing, temperature control and the sleep/wake cycle, have the LTP and LTD and hence the capacity to be modified by experience.