Posts tagged protein synthesis
Articles and news from the latest research reports.
The logistics of learning
Learning requires constant reconfiguration of the connections between nerve cells. Two new studies now yield new insights into the molecular mechanisms that underlie the learning process.
Learning and memory are made possible by the incessant reorganization of nerve connections in the brain. Both processes are based on targeted modifications of the functional interfaces between nerve cells – the so-called synapses – which alter their form, molecular composition and functional properties. In effect, connections between cells that are frequently co-activated together are progressively altered so that they respond to subsequent signals more rapidly and more strongly. This way, information can be encoded in patterns of synaptic activity and promptly recalled when needed. The converse is also true: learned behaviors can be lost by disuse, because inactive synapses are themselves less likely to transmit an incoming impulse, leading to the decay of such connections.
How exactly an individual synapse is altered without simultaneously affecting nearby nerve cells or other synapses on the same cell is a question that is central to Michael Kiebler’s research. Kiebler, a biochemist, holds the Chair of Cell Biology in the Faculty of Medicine at LMU. “It is now clear that the changes take place in the cell that is stimulated by synaptic input – the post-synaptic cell – and in particular in its so-called dendritic spines,” he says, “and particles that are known as “neuronal RNA granules” deliver mRNA molecules to these sites“. These mRNAs represent the blueprints for the synthesis of the proteins responsible for reconfiguring the synapses. Kiebler‘s team has developed a model, which postulates that these granules migrate from dendrite to dendrite, and release their mRNAs specifically at sites that are repeatedly activated. This would ensure that the relevant proteins are synthesized only where they are needed within the cell.
In spite of the potential significance of the model, the molecular mechanisms required for its realization have remained obscure. mRNA-binding proteins, including Staufen2 (Stau2) and Barentsz, are essential components of the granules, and Kiebler’s team, in collaboration with Giulio Superti-Furga’s group (CeMM, Vienna), have now used specific antibodies to isolate and characterize neuronal granules that contain either Stau2 or Barentsz.
Surprising diversity
It has generally been assumed that all neuronal RNA granules have essentially similar compositions. However, the new findings indicate that this is not the case. A comparison between Stau2- and Barentsz-containing granules reveals that they differ in about two-thirds of their proteins. “This suggests that the RNA granules are highly heterogeneous and dynamic in their composition,” says Kiebler. “And that makes sense to me, because it would mean that the granules can perform different functions depending on which mRNAs they carry.” Furthermore, the researchers have shown that the granules contain virtually none of the factors known to promote the translation of mRNAs into proteins. On the contrary, they include many molecules that repress protein synthesis. This in turn implies that the process of mRNA transport is uncoupled from the subsequent production of the proteins they encode.
In a complementary study, Kiebler’s team also characterized the mRNA cargoes associated with the granules. “Until now, none of the RNA molecules present in Stau2-containing granules in mammalian nerve cells had been defined, but we have now been able to identify many specific mRNAs,” Kiebler explains. Further experiments revealed that Stau2 stabilizes the mRNAs, allowing them to be used more often for the production of proteins. Moreover, the researchers have shown that specialized structures within these mRNAs, called “Staufen-Recognized Structures” (SRS), are essential for their recognition and stabilization by Stau2. “This allows us to propose a molecular mechanism for RNA recognition for the first time,” says Kiebler.
Taken together, the two new papers (1, 2) provide novel insights into the molecular mechanisms that underlie learning and memory. The scientists now want to dissect out the details in future studies. “In the long term, we are particularly interested in the question of how an activated synapse can alter the state of the granules and induce the production of protein,” Kiebler notes. It is becoming increasingly clear that RNA-binding proteins play essential roles in nerve cells. Disruption of their action can lead to neurodegenerative diseases and neurological dysfunction. Clearly, not only classical conditions such as Alzheimer‘s or Parkinson’s disease, in which RNA-binding proteins are always involved, but also cognitive defects or age-associated impairment of learning ability must be viewed in this context,” Kiebler concludes.
(Source: en.uni-muenchen.de)
Neuroscientists identify protein linked to Alzheimer’s-like afflictions
A team of neuroscientists has identified a modification to a protein in laboratory mice linked to conditions associated with Alzheimer’s Disease. Their findings, which appear in the journal Nature Neuroscience, also point to a potential therapeutic intervention for alleviating memory-related disorders.
The research centered on eukaryotic initiation factor 2 alpha (eIF2alpha) and two enzymes that modify it with a phosphate group; this type of modification is termed phosphorylation. The phosphorylation of eIF2alpha, which decreases protein synthesis, was previously found at elevated levels in both humans diagnosed with Alzheimer’s and in Alzheimer’s Disease (AD) model mice.
"These results implicate the improper regulation of this protein in Alzheimer’s-like afflictions and offer new guidance in developing remedies to address the disease," said Eric Klann, a professor in New York University’s Center for Neural Science and the study’s senior author.
The study’s co-authors also included: Douglas Cavener, a professor of biology at Pennsylvania State University; Clarisse Bourbon, Evelina Gatti, and Philippe Pierre of Université de la Méditerranée in Marseille, France; and NYU researchers Tao Ma, Mimi A. Trinh, and Alyse J. Wexler.
It has been known for decades that triggering new protein synthesis is vital to the formation of long-term memories as well as for long-lasting synaptic plasticity — the ability of the neurons to change the collective strength of their connections with other neurons. Learning and memory are widely believed to result from changes in synaptic strength.
In recent years, researchers have found that both humans with Alzheimer’s Disease and AD model mice have relatively high levels of eIF2alpha phosphorylation. But the relationship between this characteristic and AD-related afflictions was unknown.
Klann and his colleagues hypothesized that abnormally high levels of eIF2alpha phosphorylation could become detrimental because, ultimately, protein synthesis would diminish, thereby undermining the ability to form long-term memories.
To explore this question, the researchers examined the neurological impact of two enzymes that phosphorylate eIF2alpha, kinases termed PERK and GCN2, in different populations of AD model mice — all of which expressed genetic mutations akin to those carried by humans with AD. These were: AD model mice; AD model mice that lacked PERK; and AD model mice that lacked GCN2.
Specifically, they looked at eIF2alpha phosphorylation and the regulation of protein synthesis in the mice’s hippocampus region — the part of the brain responsible for the retrieval of old memories and the encoding of new ones. They then compared these levels with those of postmortem human AD patients.
Here, they found both increased levels of phosphorylated eIF2alpha in the hippocampus of both AD patients and the AD model mice. Moreover, in conjunction with these results, they found decreased protein synthesis, known to be required for long-term potentiation — a form of long-lasting synaptic plasticity—and for long-term memory.
To test potential remedies, the researchers examined phosphorylation of eIF2alpha in mice lacking PERK, hypothesizing that removal of this kinase would return protein synthesis to normal levels. As predicted, mice lacking PERK had levels of phosphorylated eIF2alpha and protein synthesis similar to those of normal mice.
They then conducted spatial memory tests in which the mice needed to navigate a series of mazes. Here, the AD model mice lacking PERK were able to successfully maneuver through the mazes at rates achieved by normal mice. By contrast, the other AD model mice lagged significantly in performing these tasks.
The researchers replicated these procedures on AD model mice lacking GCN2. The results here were consistent with those of the AD model mice lacking PERK, demonstrating that removal of both kinases diminished memory deficits associated with Alzheimer’s Disease.
(Source: eurekalert.org)
Hitting ‘reset’ in protein synthesis restores myelination, suggests new treatment for misfolded protein diseases, such as CMT, Alzheimer’s
Neuroscientists at UB’s Hunter James Kelly Research Institute show how turning down synthesis of a protein improves nerve, muscle function in common neuropathy.
A potential new treatment strategy for patients with Charcot-Marie-Tooth disease is on the horizon, thanks to research by neuroscientists now at the University at Buffalo’s Hunter James Kelly Research Institute and their colleagues in Italy and England.
The institute is the research arm of the Hunter’s Hope Foundation, established in 1997 by Jim Kelly, Buffalo Bills Hall of Fame quarterback, and his wife, Jill, after their infant son Hunter was diagnosed with Krabbe Leukodystrophy, an inherited fatal disorder of the nervous system. Hunter died in 2005 at the age of eight. The institute conducts research on myelin and its related diseases with the goal of developing new ways of understanding and treating conditions such as Krabbe disease and other leukodystrophies.
Charcot-Marie-Tooth or CMT disease, which affects the peripheral nerves, is among the most common of hereditary neurological disorders; it is a disease of myelin and it results from misfolded proteins in cells that produce myelin.
The new findings were published online earlier this month in The Journal of Experimental Medicine.
They may have relevance for other diseases that result from misfolded proteins, including Alzheimer’s disease, Parkinson’s, multiple sclerosis, Type 1 diabetes, cancer and mad cow disease.
The paper shows that missteps in translational homeostasis, the process of regulating new protein production so that cells maintain a precise balance between lipids and proteins, may be how some genetic mutations in CMT cause neuropathy.
CMT neuropathies are common, hereditary and progressive; in severe cases, patients end up in wheelchairs. These diseases significantly affect quality of life but not longevity, taking a major toll on patients, families and society, the researchers note.
“It’s possible that our finding could lead to the development of an effective treatment not just for CMT neuropathies but also for other diseases related to misfolded proteins,” says Lawrence Wrabetz, MD, director of the institute and professor of neurology and biochemistry in UB’s School of Medicine and Biomedical Sciences and senior author on the paper. Maurizio D’Antonio, of the Division of Genetics and Cell Biology of the San Raffaele Scientific Institute in Milan is first author; Wrabetz did most of this research while he was at San Raffaele, prior to coming to UB.
The research finding centers around the synthesis of misfolded proteins in Schwann cells, which make myelin in nerves. Myelin is the crucial fatty material that wraps the axons of neurons and allows them to signal effectively. Many CMT neuropathies are associated with mutations in a gene known as P0, which glues the wraps of myelin together. Wrabetz has previously shown in experiments with transgenic mice that those mutations cause the myelin to break down, which in turn, causes degeneration of peripheral nerves and wasting of muscles.
When cells recognize that the misfolded proteins are being synthesized, cells respond by severely reducing protein production in an effort to correct the problem, Wrabetz explains. The cells commence protein synthesis again when a protein called Gadd34 gets involved.
“After cells have reacted to, and corrected, misfolding of proteins, the job of Gadd34 is to turn protein synthesis back on,” says Wrabetz. “What we have shown is that once Gadd34 is turned back on, it activates synthesis of proteins at a level that’s too high—that’s what causes more problems in myelination.
“We have provided proof of principle that Gadd34 causes a problem with translational homeostasis and that’s what causes some neuropathies,” says Wrabetz. “We’ve shown that if we just reduce Gadd34, we actually get better myelination. So, leaving protein synthesis turned partially off is better than turning it back on, completely.”
In both cultures and a transgenic mouse model of CMT neuropathies, the researchers improved myelin by reducing Gadd34 with salubrinal, a small molecule research drug. While salubrinal is not appropriate for human use, Wrabetz and colleagues at UB and elsewhere are working to develop derivatives that are appropriate.
“If we can demonstrate that a new version of this molecule is safe and effective, then it could be part of a new therapeutic strategy for CMT and possibly other misfolded protein diseases as well,” says Wrabetz.
And while CMT is the focus of this particular research, the work is helping scientists at the Hunter James Kelly Research Institute enrich their understanding of myelin disorders in general.
“What we learn in one disease, such as CMT, may inform how we think about toxins for others, such as Krabbe’s,” Wrabetz says. “We’d like to build a foundation and answer basic questions about where and when toxicity in diseases begin.”
The misfolded protein diseases are an interesting and challenging group of diseases to study, he continues. “CMT, for example, is caused by mutations in more than 40 different genes,” he says. “When there are so many different genes involved and so many different mechanisms, you have to find a unifying mechanism: this problem of Gadd34 turning protein synthesis on at too high a level could be one unifying mechanism. The hope is that this proof of principle applies to more than just CMT and may lead to improved treatments for Alzheimer’s, Parkinson’s, Type 1 diabetes and the other diseases caused by misfolded proteins.”
(Source: buffalo.edu)
A proposed link between aging, autism, and oxidation
Like any factory, the body burns oxygen to get energy for its various needs. As a result, detrimental byproducts are released and our cells try to clean up shop with antioxidants. But as we age, this process becomes a losing battle.
“Oxidation inexorably moves us along toward an oxidized state,” said pharmaceutical sciences professor Richard Deth. “You have to deal with it progressively.”
One option is to slow down the synthesis of new proteins, a process that requires energy. Indeed, as we age, we produce fewer new proteins, which explains why our capacity for learning and healing suffer as we grow old.
Since every protein originates from instructions in the DNA, protein synthesis can be slowed down by turning off particular genes. A process called epigenetic regulation accomplishes the task by adding molecular tags on top of the genome. The protein methionine synthase regulates this process. But what regulates methionine synthase? Oxidation.
“This enzyme is the most easily oxidized molecule in the body,” said Deth, whose research on the subject was recently published in the journal PLOS ONE. The senior author for the study, Christina Muratore, received her doctorate in pharmaceutical sciences from Northeastern in 2010.
Whenever the body is under oxidative stress, Deth explained, methionine synthase, or MS, stops working. He and his team hypothesized that MS plays an important regulatory role in aging and that it might be impaired in autism, which Deth has connected to unchecked oxidative stress in previous research.
To examine their hypothesis, the researchers looked at postmortem human brain samples across the lifespan, with subjects as young as 28 weeks of fetal development to as old as 84 years. They measured the levels of a molecule called MS mRNA, which transcribes the genetic code for methionine synthase into actual protein.
As the subjects aged, their brain tissue showed lower levels of MS mRNA. But, surprisingly, the levels of the protein itself remained constant across the lifespan.
Deth and his colleagues suspect that this observed decrease in MS mRNA over our lives may act as a check in the system to save energy that we no longer have in plentiful supply and to slow down oxidative stress. “One way that the system can guard against too much protein synthesis is to restrict the amount of mRNA,” Deth said.
The team also compared MS protein and mRNA levels between brain tissue samples from autistic and normally developing subjects. Autistic brains had markedly less MS mRNA than the control samples but similar protein levels. Additionally, the age-dependent trend seen in normally developing brains was not mimicked among the autistic sample.
If decreased MS mRNA does mean decreased protein production, it’s no big deal for adults who don’t need to make new proteins as often. But for the developing brain, new proteins are critical. “Your capacity for learning might be prematurely reduced because metabolically you can’t afford it,” Deth suggested.
While the results are preliminary and will benefit from repeated studies and more investigation, Deth’s findings add to a growing body of evidence linking both aging and autism to oxidative stress.
Scientists Uncover a Previously Unknown Mechanism of Memory Formation
It takes a lot to make a memory. New proteins have to be synthesized, neuron structures altered. While some of these memory-building mechanisms are known, many are not. Some recent studies have indicated that a unique group of molecules called microRNAs, known to control production of proteins in cells, may play a far more important role in memory formation than previously thought.
Now, a new study by scientists on the Florida campus of The Scripps Research Institute has for the first time confirmed a critical role for microRNAs in the development of memory in the part of the brain called the amygdala, which is involved in emotional memory. The new study found that a specific microRNA—miR-182—was deeply involved in memory formation within this brain structure.
“No one had looked at the role of microRNAs in amygdala memory,” said Courtney Miller, a TSRI assistant professor who led the study. “And it looks as though miR-182 may be promoting local protein synthesis, helping to support the synapse-specificity of memories.”
In the new study, published in the Journal of Neuroscience, the scientists measured the levels of all known microRNAs following an animal model of learning. A microarray analysis, which enables rapid genetic testing on a large scale, showed that more than half of all known microRNAs are expressed in the amygdala. Seven of those microRNAs increased and 32 decreased when learning occurred.
The study found that, of the microRNAs expressed in the brain, miR-182 had one of the lowest levels and these decreased further with learning. Despite these very low levels, its overexpression prevented the formation of memory and led to a decrease in proteins that regulate neuronal plasticity (neurons’ ability to adapt) through changes in structure.
These findings suggest that learning-induced suppression of miR-182 is a main supporting factor in the formation of long-term memory in the amagdala, as well as an underappreciated mechanism for regulating protein synthesis during memory consolidation, Miller said.
Further analysis identified miR-182 as a repressor of proteins that control actin—a major component of the cytoskeleton, the scaffolding that holds cells together.
“We know that memory formation requires changes in dendritic spines on the neurons through regulation of the actin cytoskeleton,” Miller said. “When miR-182 is suppressed through learning it halts, at least in part, repression of actin-regulating proteins, so there’s a good chance that miR-182 exerts important control over the actin cytoskeleton.”
Miller is now interested in whether or not high levels of miR-182 accumulate in the aging brain, something that would help to explain a tendency toward memory loss in the elderly. She also notes that other research has shown that animal models lacking miR-182 had no significant physical or cellular abnormalities, suggesting that miR-182 could be a viable target for drug discovery.
(Image: stockfresh)
Neuroscientists find excessive protein synthesis linked to autistic-like behaviors
Autistic-like behaviors can be partially remedied by normalizing excessive levels of protein synthesis in the brain, a team of researchers has found in a study of laboratory mice. The findings, which appear in the latest issue of Nature, provide a pathway to the creation of pharmaceuticals aimed at treating autism spectrum disorders (ASD) that are associated with diminished social interaction skills, impaired communication ability, and repetitive behaviors.
"The creation of a drug to address ASD will be difficult, but these findings offer a potential route to get there," said Eric Klann, a professor at NYU’s Center for Neural Science and the study’s senior author. "We have not only confirmed a common link for several such disorders, but also have raised the exciting possibility that the behavioral afflictions of those individuals with ASD can be addressed."
The study’s other co-authors included researchers from the University of California, San Francisco (UCSF) and three French institutions: Aix-Marseille Universite’; Institut National de la Santé et de la Recherche Médicale (INSERM); and Le Centre National de la Recherche Scientifique (CNRS).
The researchers focused on the EIF4E gene, whose mutation is associated with autism. The mutation causing autism was proposed to increase levels of the eIF4E, the protein product of EIF4E, and lead to exaggerated protein synthesis. Excessive eIF4E signaling and exaggerated protein synthesis also may play a role in a range of neurological disorders, including fragile X syndrome (FXS).
In their experiments, the researchers examined mice with increased levels of eIF4E. They found that these mice had exaggerated levels of protein synthesis in the brain and exhibited behaviors similar to those found in autistic individuals—repetitive behaviors, such as repeatedly burying marbles, diminished social interaction (the study monitored interactions with other mice), and behavioral inflexibility (the afflicted mice were unable to navigate mazes that had been slightly altered from ones they had previously solved). The researchers also found altered communication between neurons in brain regions linked to the abnormal behaviors.
To remedy to these autistic-like behaviors, the researchers then tested a drug, 4EGI-1, which diminishes protein synthesis induced by the increased levels of eIF4E. Through this drug, they hypothesized that they could return the afflicted mice’s protein production to normal levels, and, with it, reverse autistic-like behaviors.
The subsequent experiments confirmed their hypotheses. The mice were less likely to engage in repetitive behaviors, more likely to interact with other mice, and were successful in navigating mazes that differed from those they previously solved, thereby showing enhanced behavioral flexibility. Additional investigation revealed that these changes were likely due to a reduction in protein production—the levels of newly synthesized proteins in the brains of these mice were similar to those of normal mice.
"These findings highlight an invaluable mouse model for autism in which many drugs that target eIF4E can be tested," added co-author Davide Ruggero, an associate professor at UCSF’s School of Medicine and Department of Urology. "These include novel compounds that we are developing to target eIF4E hyperactivation in cancer that may also be potentially therapeutic for autistic patients."
(Source: eurekalert.org)
Mayo Clinic Researchers Uncover Toxic Interaction in Neurons that Leads to Dementia and ALS
Researchers at Mayo Clinic in Florida have uncovered a toxic cellular process by which a protein that maintains the health of neurons becomes deficient and can lead to dementia. The findings shed new light on the link between culprits implicated in two devastating neurological diseases: frontotemporal dementia and amyotrophic lateral sclerosis, also known as Lou Gehrig’s disease. The study is published Dec. 10 in the online issue of Proceedings of the National Academy of Sciences.
There is no cure for frontotemporal dementia, a disorder that affects personality, behavior and language and is second only to Alzheimer’s disease as the most common form of early-onset dementia. While much research is devoted to understanding the role of each defective protein in these diseases, the team at Mayo Clinic took a new approach to examine the interplay between TDP-43, a protein that regulates messenger ribonucleic acid (mRNA) — biological molecules that carry the information of genes and are used by cells to guide protein synthesis — and sortilin, which regulates the protein progranulin.
"We sought to investigate how TDP-43 regulates the levels of the protein progranulin, given that extreme progranulin levels at either end of the spectrum, too low or too high, can respectively lead to neurodegeneration or cancer," says the study’s lead investigator, Mercedes Prudencio, Ph.D., a neuroscientist at the Mayo Clinic campus in Florida.
The neuroscientists found that a lack of the protein TDP-43, long implicated in frontotemporal dementia and amyotrophic lateral sclerosis, leads to elevated levels of defective sortilin mRNA. The research team is the first to identify significantly elevated levels of the defective sortilin mRNA in autopsied human brain tissue of frontotemporal dementia/TDP cases, the most common subtype of the disease.
(Image: Wikimedia Commons)
New hope for understanding autism spectrum disorders
Researchers from McGill University and the University of Montreal have identified a crucial link between protein synthesis and autism spectrum disorders (ASD), which can bolster new therapeutic avenues. Regulation of protein synthesis, also termed mRNA translation, is the process by which cells manufacture proteins.
This mechanism is involved in all aspects of cell and organism function. A new study in mice has found that abnormally high synthesis of a group of neuronal proteins called neuroligins results in symptoms similar to those diagnosed in ASD. The study also reveals that autism-like behaviors can be rectified in adult mice with compounds inhibiting protein synthesis, or with gene-therapy targeting neuroligins. Their results are published in the journal Nature.
Autism spectrum disorders (ASD) encompass a wide array of neurodevelopmental diseases that affect three areas of behaviour: social interactions, communication and repetitive interests or behaviors. According to the U.S.-based Centers for Disease Control and Prevention, 1 in 88 children suffer from ASD, and the disorder is reported to occur in all racial, ethnic, and socioeconomic groups. ASDs are almost five times more common among boys (1 in 54) than among girls (1 in 252).
“My lab is dedicated to elucidating the role of dysregulated protein synthesis in cancer etiology. However, our team was surprised to discover that similar mechanisms may be implicated in the development of ASD”, explained Prof. Nahum Sonenberg, from McGill’s Dept. of Biochemistry, Faculty of Medicine, and the Goodman Cancer Research Centre. “We used a mouse model in which a key gene controlling initiation of protein synthesis was deleted. In these mice, production of neuroligins was increased. Neuroligins are important for the formation and regulation of connections known as synapses between neuronal cells in the brain and essential for the maintenance of the balance in the transmission of information from neuron to neuron.”
“Since the discovery of neuroligin mutations in individuals with ASD in 2003, the precise molecular mechanisms implicated remain unknown,” said Christos Gkogkas, a postdoctoral fellow at McGill and lead author. “Our work is the first to link translational control of neuroligins with altered synaptic function and autism-like behaviors in mice. The key is that we achieved reversal of ASD-like symptoms in adult mice. Firstly, we used compounds, which were previously developed for cancer treatment, to reduce protein synthesis. Secondly, we used non-replicating viruses as vehicles to put a break on exaggerated synthesis of neuroligins.”
Computer modeling played an important role in this research. “By using a new sophisticated computer algorithm that we specially developed to answer Dr. Sonenberg’s questions, we identified the unique structures of mRNAs of the neuroligins that could be responsible for their specific regulation,” explained Prof. François Major, of the University of Montreal’s Institute for Research in Immunology and Cancer and Department of Computer Science.
The researchers found that dysregulated synthesis of neuroligins augments synaptic activity, resulting in an imbalance between excitation and inhibition in single brain cells, opening up exciting new avenues for research that may unlock the secrets of autism.
“The autistic behaviours in mice were prevented by selectively reducing the synthesis of one type of neuroligin and reversing the changes in synaptic excitation in cells,” explained Prof. Jean-Claude Lacaille at the University of Montreal’s Groupe de Recherche sur le Système Nerveux Central and Department of Physiology. “In short, we manipulated mechanisms in brain cells and observed how they influence the behaviour of the animal.” The researchers were also able to reverse changes in inhibition and augment autistic behaviors by manipulating a second neuroligin. “The fact that the balance can be affected suggests that there could be a potential for pharmacological intervention by targeting these mechanisms,” Lacaille concluded.
(Source: nouvelles.umontreal.ca)
The Fabric for Weaving Memory
The details of memory formation are still largely unknown. It has, however, been established that the two kinds of memory – long term and short term – use different mechanisms. When short-term memory is formed, certain proteins in the nerve cells (neurons) of the brain are transiently modified. To establish long-term memory, the cells have to synthesize new protein molecules. This has been shown in experiments with animals. When drugs were used to block protein synthesis, the treated animals were not able to form long-term memory.
The precise mechanism by which the newly synthesized proteins regulate memory formation is still poorly understood. They are thought to strengthen existing connections between neurons, as well as establish new connections. Both processes are required for long-term memory formation.
A nerve cell in the brain makes connections with tens of thousands of other nerve cells through so-called synapses. When memory is formed, only specific synapses, which are activated by a specific experience are modified. The mechanism of how the synthesis of new proteins can be restricted to these activated synapses has been unclear. Neurobiologists have postulated the existence of “synaptic tags”. One of the candidates is a family of proteins known to regulate local protein synthesis, the CPEB family of proteins. These proteins have been known for some time to perform important tasks during embryonic development, and recently have been identified in neuronal synapses.
In 2007, Krystyna Keleman, a neuroscientist at the Research Institute of Molecular Pathology (IMP) in Vienna, was able to show that fruit flies require CPEB proteins for long-term memory formation.
To study memory formation, the researchers at the IMP looked at the sexual behavior of flies. After copulation, female flies loose interest in the courtship advances of males. Male flies must learn – by trial and error – that only virgin females are receptive. The key to telling them apart is their smell.