Researchers Find Enzyme Crucial to Preservation of Memories
September 21, 2001— Using a technique to eliminate the function of one enzyme
in a restricted memory-related region in the brains of mice, researchers have
shown that the enzyme is important in consolidating long-term memories.
According to the researchers, their experiments — which showed that defects in
a key biochemical signaling pathway were responsible for the animals’
inability
to improve their long-term memory in a series of maze tests — constitute a
powerful approach to understanding molecules involved in learning and memory.
In an article published in the September 21, 2001, issue of Cell, Howard
Hughes
Medical Institute investigator Susumu Tonegawa and colleagues at the
Massachusetts Institute of Technology and the Vollum Institute reported that
elimination of the enzyme, calcium-calmodulin dependent kinase (CaMKIV), in
the
forebrains of mice had profound effects on signaling pathways in the brain and
learning behavior.
The scientists began their studies to clarify the enzyme’s role in late
long-term potentiation (L-LTP), the process by which enduring memories are
established through a mechanism of activating genes that trigger protein
synthesis. This protein synthesis, in turn, alters the synapses — connections
between neurons — and “etches” permanent memory pathways.
“CaMKIV had been implicated in long-term memory pathways in the past, but
previous studies had involved global knockout of the enzyme in the entire
animal,” said Tonegawa. “Such knockouts gave inconsistent results because they
affected the whole brain throughout development. We decided to use a technique
to inhibit the protein only in the forebrain, which is more involved in higher
brain function.”
Tonegawa said that other research groups had attempted to knock out a protein
called CREB, which is involved in turning on gene transcription in L-LTP, and
which was believed to be activated by CaMKIV. The results of these studies
were
inconclusive, Tonegawa said, because there appeared to be multiple forms of
CREB that could compensate for any knockout.
Tonegawa and his colleagues used a genetic technique that allowed them to
replace the normal CaMKIV with a “dominant negative” mutant enzyme that would
be produced only in the forebrains of the mice. Dominant negative enzymes have
all of the characteristics of the functioning enzyme — such as an ability to
bind normally to other molecules — but they lack the ability to carry out an
appropriate enzymatic reaction.
The scientists first studied the molecular details of the lack of CaMKIV
activity in brain slices from the transgenic mice. They discovered that the
base level of CaMKIV activity in the mouse brains was normal, but when
chemicals were added that mimicked the conditions of neuronal activity, as in
memory formation, the enzyme function was significantly lower. The brain slice
studies also revealed that CREB activation by phosphorylation in the
transgenic
mice was suppressed, strongly implicating a role for the CaMKIV in normal CREB
activation as a result of neuronal activity.
Experiments with brain slices also revealed that the transmission of nerve
impulses in the transgenic mice was normal, except under conditions mimicking
protein-synthesis-dependent L-LTP.
“These results pinpointed for us the role of CaMKIV in the
protein-synthesis-dependent type of LTP,” emphasized Tonegawa. “This is very
important, because in the past people have published studies implicating
another enzyme, called protein kinase A, in LTP. However, that enzyme was not
specific to the protein-synthesis-dependent type of LTP.”
With clear physiological evidence that they had specifically disrupted the
CaMKIV pathway, the researchers next tested how well the transgenic mice could
consolidate memories of a water maze. The mice were placed in a pool of water
made opaque by floating beads, and required to find a platform submerged just
beneath the surface. The transgenic mice initially learned the task as well as
normal mice, but as training continued, they became significantly less able to
find the platform.
“Thus, while these mice have a normal ability to acquire memories, they have
problems converting those memories into a long-term form,” said Tonegawa.
However, he noted, maze experiments still present problems in interpretation.
“This training takes place over a two-week period, so the memory acquisition
and consolidation processes are superimposed,” said Tonegawa. “Thus, it is
difficult to know whether the deficit is primarily in the acquisition phase or
the consolidation phase.”
In an additional set of experiments, the scientists compared normal and
transgenic animals’ ability to acquire and consolidate the memory that
involves
associating a mild shock to the footpads to the specific context of the
chamber
in which the shock is administered. In these experiments, memory acquisition
could be more clearly separated from memory consolidation, said Tonegawa.
These
experiments demonstrated that the CaMKIV-deficient mice could learn to
associate the shocks to the chamber context, but they had difficulties in
converting such memories to long lasting memories, said Tonegawa.
“Our conclusion from these tests was that the CaMKIV pathway was primarily
involved in memory consolidation and retention,” he said.
Tonegawa noted that memory consolidation in the transgenic animals was not
completely extinguished, suggesting that there may be parallel signaling
pathways involved in consolidation, or that there may have been incomplete
knockout of CaMKIV activity.
“However, we believe that further studies using this technique will allow us
to
dissect in greater detail the differential roles and interactions of these
signal transduction pathways, and how they contribute to this very complex
mechanism of memory consolidation,” he said. “Also, we want to know which
genes
are activated in this process and how these gene products helps establish
these
long-term changes in synaptic strengths.”
http://www.hhmi.org/news/tonegawa.html
--- --- --- --- ---
Useless hypotheses, etc.:
consciousness, phlogiston, philosophy, vitalism, mind, free will, qualia,
analog computing, cultural relativism, GAC, Cyc, Eliza, cryonics, individual
uniqueness, ego, human values, scientific relinquishment
We won't move into a better future until we debunk religiosity, the most
regressive force now operating in society.
Everything that can happen has already happened, not just once,
but an infinite number of times, and will continue to do so forever.
(Everything that can happen = more than anyone can imagine.)
This archive was generated by hypermail 2b30 : Fri Oct 12 2001 - 14:40:54 MDT