Sushi and the science of synapses
Page 2: A filter for environmental 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, but its capacity is limited. Stored content is quickly lost when our attention wavers, or is replaced by later input relevant to the task now in hand. For durable storage, sensory impressions and experiences must be laid down in long-term memory.
A small region located in the brain’s temporal lobes plays a critical role in 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 It is also responsible for expanding storage capacity, and causing outdated entries in long-term memory to be forgotten – by degrading unused connections between neurons.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
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 between synapses.
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.
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 logistics of transport and quality-control in nerve cells are formidably 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.
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 RNA-binding 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 synapses in the case of Staufen2. If this protein is inactivated, synapses are 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.
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 contain the short structured nucleotide 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“?
The learning synapse must be in a particular 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.