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insight LMU / Issue 3, 2015
Neurobiology
Sushi and the science
of synapses
By Martin Thurau
Source: Deerinck, NCMIR/SPL/Picture Alliance
What is the molecular basis of learning? Here LMU biochemist Michael Kiebler shares his insights
into how associative learning is encoded in the brain.
A visit to a Japanese restaurant in the
company of Michael Kiebler, Professor
of Cell Biology at LMU’s Center for Biomedical Research, might be very enlightening. Biochemist Kiebler is
interested in elemental operations, and
he often mentions “belt sushi” – not with
reference to the food, but to the logistics
of self-service. Sushi lovers are often
tempted by a whole range of makis and
sashimis sedately moving by on a conveyor belt, and each guest makes his
own selection. The sushi belt, Kiebler
says, provides an apt metaphor for the
problem he works on: He wants to know
how the connections between nerve
cells are modified during the process of
learning. And one aspect of how such
modifications are targeted to the correct
locations in neural networks indeed
recalls how sushi restaurants deliver
delicacies to their guests.
The analogy may sound far-fetched, but
it may nevertheless help make sense of
a highly complex process, for how the
human brain really works and what
happens when we learn something new
is not understood in detail. One of the
central problems in modern neuroscience is how the associations of ideas
that underlie associative learning are
actually represented in the brain. That
new impressions and experiences are
linked to long-lived changes in the
functional architecture of the brain is
now an established fact. “In the course
of a conversation for example,” Kiebler
remarks, “the brain is remodeled. It
takes on a different form from before.”
One trillion connections
generic nerve cell consists of a cell body
that contains the nucleus, a long primary fiber called an axon that acts as a
transmission cable, and a forest of shorter processes called dendrites that detect
incoming signals. Each dendrite itself
bears a multiplicity of synapses, many of
them in the form of short protrusions
called dendritic spines. The nerves are
the brain’s interface with its environment. When something “out there”
touches an arm, for instance, “ion channels” in sensory nerves in the skin at
that point are activated. This causes a
change in the electrical potential across
their cell membranes (“depolarization”)
that propagates as an “action potential”
along their axons. When it reaches the
synapse, the excitatory impulse is passed
to the neighboring cell. In fact, the physi­
cal gap between synapses on adjacent
neurons is bridged by the release of a
“neurotransmitter”, a chemical messenger which depolarizes the post-synaptic
cell, sending the signal on to the somatic
sensory cortex in the brain.
The brain is always being restructured:
New patterns of neural connectivity, mediated by structures called synapses, are
set up between its constituent nerve
cells, existing networks are extended or
otherwise modified, links are forged to
already stored information, obsolete
contacts are eliminated. Repeated stimulation of sets of neurons is associated
with enhanced responsiveness of the
synaptic contacts between them – the
phenomenon of synaptic plasticity. In basic – and admittedly reductionist – neurobiological terms, learning involves no
more than the storage of novel patterns
of synaptic connections between different parts of the brain for later use. How is
this remodeling done? What kinds of
command-and-control systems underlie
this process? What is the molecular basis
of learning?
For whom the bell tolls
To say that the brain is highly complex is
a gross simplification: Its 100 billion or
so nerve cells and the myriad connections between them constitute an impenetrable maze: Each neuron is linked
to as many as 10,000 others, giving a
grand total of some 1,013 connections. A
Transmission of information between
nerve cells during the processes of
learning and recall is accomplished by
this same electrophysiological principle
of alternating electrical and chemical
signals, but the circuitry involved follows its own specific logic. What exactly
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happens when we, for example, learn to
associate a certain face with a telephone
number or an English word with the
meaning of its German counterpart?
Even in the case of classical conditioning,
this sort of learning is at work. Pavlov’s
dogs not only salivated when confronted
with a bowl of food, they learned to associate its appearance with a prior signal
and began to salivate when a bell rang.
In other words, associative learning involves the linkage, storage and recall of
at least two different snippets of information. Initially, the ringing bell has no
semantic connotation with feeding. Only
when it is associatively coupled to the
expectation of food does it acquire such
a meaning.
(“postsynaptic”) cell requires a relatively
strong stimulus from the presynaptic
cell to initiate an action potential and
fire in its turn. However, if a stimulus is
repeated in quick succession, the evoked
potential can subsequently – even hours
later – be triggered by a much weaker
impulse: Repeated stimulation makes
synaptic transmission more efficient,
and if these neurons also fire in phase
with each other, synaptic efficiency is
further enhanced.
at a time when the postsynaptic cell is
already fully depolarized. Then – and
only then – a special glutamate receptor
in the membrane of the post-synaptic
cell – the NMDA receptor – comes into
play. In its resting state, the pore of this
receptor, through which charged ions
would otherwise flow into the cell to
initiate an action potential, is blocked by
a magnesium ion. However, prior depolarization of the cell, mediated by a
glutamate-gated ion channel called
AMPA, simultaneously “unplugs” the
An “extremely cool” mechanism
NMDA channel, allowing calcium ions to
flow into the post-synaptic cell. This in
Much of what we know about LTP at turn induces the insertion of further
the physiological level comes from the AMPA receptors into the dendrites,
work done by Nobel Laureate Eric Kandel making the post-synaptic cell more sensitive to excitation – an “extremely cool”
mechanism, as Kiebler points out.
One further step is required to fix this
change: Continuing stimulation sets a
cascade of chemical reactions in train,
and a second intracellular messenger
triggers the synthesis of specific proteins that “permanently” enhance the
synapse’s responsiveness: The potentiated synapse has now “learned” to react
to very weak (and uncoupled) stimuli.
But, of course, not all incoming stimuli
are recorded on our mental hard-disk.
Sensory memory acts as a sort of filter
for environmental stimuli. It enables us
to repeat a sentence even if we haven’t
really been paying attention, but such
traces are rapidly erased. Short-term
memory retains information for longer,
A major knowledge hub: The neurons (red and blue) in the hippocampus play a critical
but its capacity is limited. Stored content
role in associative learning. Source: Deerinck, NCMIR/SPL/Picture Alliance
is quickly lost when our attention wavers,
or is replaced by later input relevant to
So how are new neuronal connections at Columbia University in New York the task now in hand. For durable storage,
formed during the process of learning, (Kiebler was a postdoc in his group). sensory impressions and experiences
and how are they stabilized? Neuro­ The excitatory neurotransmitter (in this must be laid down in long-term memory.
biologists believe that the phenomenon case glutamate) is secreted in a succesof long-term potentiation (LTP) plays a sion of discrete packets. It turns out that A small region located in the brain’s
central role. Normally, the receiving LTP occurs if the pre-synaptic cell fires temporal lobes plays a critical role in
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this last process. “The hippocampus is
involved in all associative learning,”
Kiebler remarks – including all of our
factual knowledge. The hippocampus is
our working memory, and the information processed here is passed to various
regions in the cortex for long-term storage: Visual impressions end up in the
visual cortex, semantic information in
the language centers, acoustic data in
the auditory cortex. Strikingly, there is
no central store for long-term memories,
no card index, in which engrams – the
neuronally encoded substrates of our
memories – are laid away.
The hippocampus not only generates
new connections, new nerve cells are
also produced there, even during adult
life. This structure organizes the recall
of stored information for comparison
with new input and can be viewed as the
‘hub’ of knowledge. It is also responsible
for expanding storage capacity, and
causing outdated entries in long-term
memory to be forgotten – by degrading
unused connections between neurons.
A day that everyone remembers
In fact, the diverse classes of memories
stored in the brain are organized in a
modular fashion. Learning to play an instrument, for instance, has a lot to do
with the repeated rehearsal of precise
sequences of movements. This type of
motor learning is mediated by the striatum, a component of the basal ganglia.
complex,” Kiebler explains. The mRNAs
must be properly packaged and correctly
addressed to ensure that they reach the
“learning” synapse. The material must
arrive in good condition, so that synthesis of the required proteins occurs at the
intended synapse and not at some other
one closer to the cell body.
As we have seen, synaptic plasticity permits the brain constantly to restructure
itself. Where then does the building
material come from? This is actually a
more complicated issue in neurons than
in many other cell types. For the cell
body – where most proteins are normally
synthesized – lies a long way from the
modifiable synapse to which they must
be delivered. However, it is now clear
that a significant fraction of proteins
destined for the synapse are actually
made nearby, because the cell actively
transports the genetic blueprints for
synaptic proteins – in the form of messenger RNAs – to dendritic trees that are
relatively remote from the cell nucleus,
where the mRNAs are produced.
The growth of dendritic trees
The mRNAs are packed for the journey
in so-called granules built of specialized
proteins that bind to specific mRNAs and
perform important regulatory functions
on the way. Kiebler’s team has isolated
and characterized several of these RNAbinding proteins, including Staufen2,
Barentsz and Pumilio2. These experiments showed that the protein composition of the granules is surprisingly
variable. This implies that different
granules serve different functions depending on the nature of their mRNAs,
Kiebler explains.
Kiebler’s group has elucidated the role
of the RNA-binding proteins at learning
“The logistics of transport and quality- synapses in the case of Staufen2. If this
control in nerve cells are formidably protein is inactivated, synapses are
The brain not only records dry facts. Indeed, as we all know, emotionally
charged events are especially difficult to
forget. “All of us remember even incidental details of our first date or the
birth of a child,” says Kiebler. Nobody
has forgotten the shock of seeing the
airliner plow into the Twin Towers on
9/11. Such emotion-laden memories are
processed by a brain nucleus called the
amygdala, which, like the hippocampus
(to which it is functionally related,
though anatomically distinct), is part of
the limbic system. Clearly, the hormones
secreted when we experience events
that provoke strong emotions, promote
the formation of particularly stable links How is the hunger of learning synapses satisfied? Michael Kiebler studies protein
transport and synapse modification. Source: Jan Greune
between synapses.
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malformed and dysfunctional. When the
researchers restored its function in their
cell cultures, synaptic function was rescued. Moreover, the level of Pumilio2 in
nerve cells was found to regulate the
pattern of growth of the dendritic trees
and synapse-bearing spines. RNA-binding proteins, Kiebler adds, are also
known to play a role in neurodegenerative syndromes such as Alzheimer‘s or
Parkinson’s disease. In light of this finding, it would be worthwhile to ask
whether and how they contribute to cognitive disturbances or learning deficiencies in the elderly.
sequences recognized by Staufen2 cannot be translated until it is removed. The
protein thus effectively prolongs the lifetime of the mRNA templates, and precludes premature synthesis of the
proteins they encode. Indeed, all of the
mRNAs found in the granules contain
sequence signatures that serve as lading
bills, which specify the address, the nature of the content and its intended use.
And the sushi belt?
Dedicated molecular machines transport
the granules along the microtubules of
the cytoskeleton that run into and stabilize the dendrites and their spines. This
is where Kiebler invokes running sushi.
For the RNA granules are presented to
synapses like the sushi on that conveyor
belt. Indeed, Kiebler extends the metaphor: The sushi-lover can take as many
of the appetizing morsels as he needs to
satisfy his hunger. But what characterizes a learning synapse as “hungry“?
Interestingly, the RNA granules do not
contain factors that stimulate the translation of their mRNAs into protein. On
the contrary, Kiebler‘s team found many
molecules that inhibit translation. Kiebler
therefore concludes that, for security
reasons so to speak, transport of mRNAs
to synapses is uncoupled from the subsequent production of the proteins they
encode. Staufen2 apparently acts as a
certificate of freshness. mRNAs that The learning synapse must be in a parcontain the short structured nucleotide ticular physiological state to reach out for
the goodies. It must be tagged in some
way, and Kiebler would love to know
how. Some time ago, he discovered that
many Staufen2-containing granules
transport RNAs that code for one of the
two subunits of the enzyme CaMKII. So
this component is destined to be synthesized on site, at the synapse. The other
subunit, however, is made in the cell
body. Only when the two come together
is the active enzyme formed. “Now everything fits,” says Kiebler. To be translated
into proteins the mRNAs must interact
specifically with a learning synapse, and
the locally produced subunit then acts
like the extended arm of the hungry synapse, reaching out for the missing part,
which diffuses from the cell body. And in
this context, CaMKII is not just any enzyme: It is a calcium-dependent modifier of protein function: Only when the
crucial NMDA channel is open, permitting calcium ions to flow into the learning synapse, can it be activated to
perform its crucial role in implementing
LTP. One might say that such synapses
are keen to learn – but perhaps that
pushes the metaphor too far!
Prof. Dr. Michael Kiebler
Chair of Cell Biology at LMU’s Biomedical Center. Born in 1964, Kiebler
studied Chemistry and earned a doctorate in Biochemistry at LMU, before
going on to work as a postdoc at Columbia University in New York, and at
the European Molecular Biology Laboratory in Heidelberg. He then joined
the Max Planck Institute for Developmental Biology in Tübingen and later
headed the Section for Molecular Cell Biology at the Medical University of
Vienna, before moving to Munich in 2012.
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The original article appeared in ”Einsichten – das Forschungsmagazin No. 1, 2015“, LMU‘s German-language research magazine.
Translation: Paul Hardy, Copyright: Ludwig-Maximilians-Universität München, 2015.
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