X-Message-Number: 983
Newsgroups: sci.cryonics
From:  (kevin.q.brown)
Subject: New Synapses for Aplysia
Date: Mon, 13 Jul 1992 21:41:52 GMT
Keywords: memory synapse LTP

[ One of the main questions for cryonicists is whether or not memory
  survives cryonic suspension.  This is difficult to determine for
  certain, since we do not yet completely understand how memory works.
  But we are accumulating a lot of intriguing clues.  This message
  from a recent issue of Periastron concerns some of those clues.
  It is posted with permission of the author Thomas Donaldson
  <>.  (Note: The diagrams are missing because
  they could not easily be transcribed to the email version.) - KQB ]


NEW SYNAPSES FOR APLYSIA
by Thomas Donaldson
Periastron, P.O. Box 2365, Sunnyvale, CA 94087

For those who may not have been following all the work on memory, Aplysia
is the generic name of a sea mollusc studied intensively by Eric Kandel
and many of those examining his ideas.  Its nervous system is simple
enough to have been completely mapped; it also allows intervention both
in the living animal and in laboratory preparations because, like all
molluscs, its nerves have no myelin sheaths.

By now Kandel and others have studied memory in Aplysia quite closely.
As with mammals, Aplysia shows signs of LTP (long term potentiation, a
process by which repeated stimulation will make a nerve fire more
readily, and so may underlie learning itself).  Still, even Eric Kandel
would not go so far as to identify LTP as the fundamental mechanism of
memory.  Among other reasons against that, even synapses undergo constant
renewal: so we would still need to know just why that renewal does not
destroy the memory they might contain.  Currently, many neuroscientists
believe that the only viable theory for true long term memory would
explain it by an actual increase in the number of synapses connecting one
neuron with another.  Such a process would be as stable as any other
process of growth and development, and would use very much the same
biochemistry.

For Aplysia, however, very little had yet been done to discover any such
process.  But the purpose of studying Aplysia has been to uncover the
processes by which we (or at least Aplysia) acquire a true long term
memory.

Eric Kandel and 7 other scientists, each with their own separate
expertise, have now combined to study such a growth of new synapses in
Aplysia.  They have not only shown that it happens, but also uncovered
some of the chemical processes by which it happens.  And finally, of
course, they have published their results in two papers in SCIENCE (M
Mayford, A Barzilai, F Keller, S Schacher, E Kandel, SCIENCE 256(1992)
638-644; CH Bailey, M Chen, F Keller, E Kandel, SCIENCE 256(1992)
645-649).

These researchers have all known for some time that an increase in number
of connections happens in Aplysia when one particular kind of connection,
between sensory neurons and motor neurons to the gill becomes sensitized
by primitive learning.  The first paper listed above describes their use
of molecular biology to find out just what happens to cause this increase
in connections.  It was easy to show that the process needed protein
synthesis, since inhibitors of protein synthesis would stop it.  It was
also easy, in laboratory preparations, to create such a reaction without
training: simple application of serotonin (one of the nerve transmitters)
to a synapse would result in growth of new connections not long
afterwards.

To find out what happened, these researchers report first using simple
assays to show that 5 different proteins decreased their levels when this
growth of new synapses began.  They could isolate 4 of these, and then
actually use a library of Aplysia DNA to match each one to its
corresponding DNA.

As it turned out, they all came from one DNA sequence.  (This isn't as
strange as it may sound: our immune system depends on the fact that only
a few genes, by systematic modifications, can generate very many
different protein molecules to attack foreign substances.  In fact,
resemblances exist between these molecules, others in our own brain, and
still others from the immune system).  After finding that DNA sequence, a
good deal about these molecules became clear.

First, although not identical, they closely resembled a class of proteins
frequently occurring in our own brains.  They are called NCAMs, which
stands for Neural Cell Adhesion Molecules.  True to their name, NCAMs
normally exist on the outer cell walls of neurons, and act to attach
these neuron surfaces together.  In humans and other mammals, NCAMs also
serve important roles in growth and development of our brains.  The
proteins found in Aplysia, although not identical, resembled NCAMs in
their general structure and several other important ways.  These
scientists therefore baptized them as apCAMs.

With this information in hand, the next step was to discover just what
happened to these proteins when "learning" took place in a synapse.
These neuroscientists did so by studying the response of Aplysia nerve
cells in culture.  They first labelled the apCAMs with a fluorescent dye,
then applied serotonin (to imitate the effect of learning).  Those apCAMs
on cell walls nearby moved inside the cell, where they were destroyed.
Several experiments showed quite well that when apCAMs on the cell
surface went down, the nerve cells began to form neurites, growing many
branches outward.

For NCAMs, even small changes in their amount on neural cell surfaces
cause dramatic changes in growth of neurites.  The apCAMs did the same.
Although this growth of neurites doesn't directly form new synapses, it
sets up the preconditions such formation requires.

The second paper listed studies these reactions using electron
microscopy, again labelling apCAM molecules to follow what happens to
them.  Within an hour after stimulation with serotonin, nearby cell
surfaces lost 50% of their apCAMs, which labelling showed had somehow
entered the cell.  The authors of this second paper show some very good
electron micrographs of how this happens: pockets in the cell surface
containing apCAMs form, then finally separate as little globes inside the
cell (see Diagram XX).  The apCAMs they contain are broken down; the cell
membranes which held them are then returned to the outer cell membrane,
devoid of apCAMs.  This process occurs very actively at places where one
neuron wall contacts another.

Careful study of these results tells us how little we still understand of
the processes linking growth of new synapses, and LTP in the old.  The
system of apCAMs Kandel, Barzilai, and their coworkers have uncovered
only gives part of the processes involved.  On the other hand, their
observations of formation of new synapses in Aplysia tell us that even in
Aplysia new synapses must play an essential role in true long term
memory.  Finally, these experiments currently fall among a very small
number done by neuroscientists on memory using molecular biology.
Cloning, DNA libraries, and sequencing of genes and proteins provide
major new handles with which to grasp an understanding of memory.

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