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insightLMU Research 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 1 insightLMU / Issue 3, 2015 Research 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 2 insightLMU / Issue 3, 2015 Research 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. 3 insightLMU / Issue 3, 2015 Research 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. 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. 4