Greater Rates of Mitochondrial Mutations Discovered in Children Born to Older Mothers

The discovery of a “maternal age effect” by a team of Penn State scientists that could be used to predict the accumulation of mitochondrial DNA mutations in maternal egg cells — and the transmission of these mutations to children — could provide valuable insights for genetic counseling. These mutations cause more than 200 diseases and contribute to others such as diabetes, cancer, Parkinson’s disease, and Alzheimer’s disease. The study found greater rates of the mitochondrial DNA variants in children born to older mothers, as well as in the mothers themselves. The research will be published in the early online edition of the Proceedings of the National Academy of Sciences on October 13, 2014.

Mitochondria are structures within cells that produce energy and that contain their own DNA. “Many mitochondrial diseases affect more than one system in the human body,” said Kateryna Makova, professor of biology and one of the study’s primary investigators. “They affect organs that require a lot of energy, including the heart, skeletal muscle, and brain. They are devastating diseases and there is no cure, so our findings about their transmission are very important.”

The multidisciplinary research team set out to learn whether maternal age is important in the accumulation of mitochondrial DNA (mtDNA) mutations, both in the mother and in the child as a result of transmission. Collaborating with Ian Paul, a pediatrician at the Penn State Milton S. Hershey Medical Center, they took samples of blood and of cells inside the cheek from 39 healthy mother-child pairs. Because mtDNA is inherited only maternally, paternal mtDNA was not a factor in the study. Studying healthy individuals gave the researchers a baseline for future studies of disease-causing mutations.

Through DNA sequencing, they found more mutations in blood and cheek cells in the older mothers in the study. Maternal age of study participants ranged from 25 to 59. “This finding is not surprising,” Makova said, “because as we age, cells keep dividing, and therefore we will have more mutant genes.” But finding greater rates of mutations in children born to the older mothers did come as a surprise. The researchers believe a similar mutation process is occurring both in the cells of the mothers’ bodies and in their germ lines.

The study led to another important discovery about egg-cell development. Although it was known that developing egg cells go through a “bottleneck” period that decreases the number of mtDNA molecules, scientists didn’t know how small or large this bottleneck is. “If the bottleneck is large, the genetic makeup of the mother’s mitochondria will be passed to her children,” Makova explained. “However, if it is tiny — if there is a severe decrease in mitochondrial molecules during the egg-cell development — then the genetic makeup of the child might differ dramatically from that of the mother. What we discovered is that this bottleneck is indeed very small.”

This finding is especially important for mothers who have a mitochondrial disease. For many mitochondrial diseases, 70 to 80 percent of molecules need to have the disease-causing variant for the disease to manifest itself. But for others, only 10 percent of the mtDNA molecules with the variant are needed to cause disease. “If the bottleneck is very small, as we’ve found in our study, these percentages can change dramatically,” Makova said. “Knowing the size of the bottleneck allows us to predict, within a range, the percentage of disease-carrying molecules that will be passed on to the child.”

Knowledge about both the maternal age effect and the bottleneck size is useful in family planning. “We have some predictive power now and can assist genetic counselors in advising couples about the chances of mitochondrial diseases being passed to the next generation,” Makova said. “Everyone is concerned about Down syndrome because that is a common genetic problem. We have now added another set of genetic disorders that also might be affected by the age of the mother. It is good for couples to have this knowledge as they make family-planning decisions.”

Aluminium and its likely contribution to Alzheimer’s disease

A world authority on the link between human exposure to aluminium in everyday life and its likely contribution to Alzheimer’s disease, Professor Christopher Exley of Keele University, UK, says in a new report that it may be inevitable that aluminium plays some role in the disease.

He says the human brain is both a target and a sink for aluminium on entry into the body – “the presence of aluminium in the human brain should be a red flag alerting us all to the potential dangers of the aluminium age. We are all accumulating a known neurotoxin in our brain from our conception to our death. Why do we treat this inevitability with almost total complacency?”

Exley, Professor in Bioinorganic Chemistry, Aluminium and Silicon Research Group in The Birchall Centre, Lennard-Jones Laboratories at Keele University, writes in Frontiers in Neurology about the ‘Aluminium Age’ and its role in the ‘contamination’ of humans by aluminium. He says a burgeoning body burden of aluminium is an inevitable consequence of modern living and this can be thought of as ‘contamination’, as the aluminium in our bodies is of no benefit to us it can only be benign or toxic.

Professor Exley says: “The biological availability of aluminium or the ease with which aluminium reacts with human biochemistry means that aluminium in the body is unlikely to be benign, though it may appear as such due to the inherent robustness of human physiology. The question is raised as to ‘how do you know if you are suffering from chronic aluminium toxicity?’ How do we know that Alzheimer’s disease is not the manifestation of chronic aluminium toxicity in humans?

“At some point in time the accumulation of aluminium in the brain will achieve a toxic threshold and a specific neurone or area of the brain will stop coping with the presence of aluminium and will start reacting to its presence. If the same neurone or brain tissue is also suffering other insults, or another on-going degenerative condition, then the additional response to aluminium will exacerbate these effects. In this way aluminium may cause a particular condition to be more aggressive and perhaps to have an earlier onset - such occurrences have already been shown in Alzheimer’s disease related to environmental and occupational exposure to aluminium.” 

Professor Exley argues that the accumulation of aluminium in the brain inevitably leads to it contributing negatively to brain physiology and therefore exacerbating on-going conditions such as Alzheimer’s disease. He suggests that this is a testable hypothesis and offers a non-invasive method of the removal of aluminium from the body and the brain. He says the aluminium hypothesis of Alzheimer’s disease will only be tested if we are able to lower the body and hence brain burden of aluminium and determine if such has any impact upon the incidence, onset or aggressiveness of Alzheimer’s disease.

Professor Exley adds: “There are neither cures nor effective treatments for Alzheimer’s disease. The role of aluminium in Alzheimer’s disease can be prevented by reducing human exposure to aluminium and by removing aluminium from the body by non-invasive means. Why are we choosing to miss out on this opportunity? Surely the time has come to test the aluminium hypothesis of Alzheimer’s disease once and for all?”

(Image credit)

Disputed theory on Parkinson’s origin strengthened

Parkinson’s disease is strongly linked to the degeneration of the brain’s movement center. In the last decade, the question of where the disease begins has led researchers to a different part of the human anatomy. In 2003, the German neuropathologist Heiko Braak presented a theory suggesting that the disease begins in the gut and spreads to the brain. The idea has since, despite vocal critics, gained a lot of ground. Researchers at Lund University in Sweden now present the first direct evidence that the disease can actually migrate from the gut to the brain.

The so-called Braak’s hypothesis proposes that the disease process begins in the digestive tract and in the brain’s center of smell. The theory is supported by the fact that symptoms associated with digestion and smell occur very early on in the disease.

Researchers at Lund University have previously mapped the spread of Parkinson’s in the brain. The disease progression is believed to be driven by a misfolded protein that clumps together and “infects” neighboring cells. Professor Jia-Yi Li’s research team has now been able to track this process further, from the gut to the brain in rat models. The experiment shows how the toxic protein, alpha-synuclein, is transported from one cell to another before ultimately reaching the brain’s movement center, giving rise to the characteristic movement disorders in Parkinson’s disease.

“We have now been able to prove that the disease process actually can travel from the peripheral nervous system to the central nervous system, in this case from the wall of the gut to the brain. In the longer term, this may give us new therapeutic targets to try to slow or stop the disease at an earlier stage”, says Professor Jia-Yi Li, research group leader for Neural Plasticity and Repair at Lund University.

The research team will now carry out further studies in which the mechanisms behind the transport of the harmful protein will be examined in detail. The current study suggests that the protein is transferred during nerve cell communication. It is at this point of interaction that the researchers want to intervene in order to put a stop to the further spread of the disease.

(Image caption: Making “scents” of new cells in the brain’s odor-processing area. Adult-born cells travel through the thin rostral migratory stream before settling into the olfactory bulb, the large structure in the upper right of the image. Courtesy of the Belluscio Lab, NINDS)

Scientists sniff out unexpected role for stem cells in the brain

For decades, scientists thought that neurons in the brain were born only during the early development period and could not be replenished. More recently, however, they discovered cells with the ability to divide and turn into new neurons in specific brain regions. The function of these neuroprogenitor cells remains an intense area of research. Scientists at the National Institutes of Health (NIH) report that newly formed brain cells in the mouse olfactory system — the area that processes smells — play a critical role in maintaining proper connections. The results were published in the October 8 issue of the Journal of Neuroscience. 

“This is a surprising new role for brain stem cells and changes the way we view them,” said Leonardo Belluscio, Ph.D., a scientist at NIH’s National Institute of Neurological Disorders and Stroke (NINDS) and lead author of the study.

The olfactory bulb is located in the front of the brain and receives information directly from the nose about odors in the environment. Neurons in the olfactory bulb sort that information and relay the signals to the rest of the brain, at which point we become aware of the smells we are experiencing. Olfactory loss is often an early symptom in a variety of neurological disorders, including Alzheimer’s and Parkinson’s diseases.

In a process known as neurogenesis, adult-born neuroprogenitor cells are generated in the subventricular zone deep in the brain and migrate to the olfactory bulb where they assume their final positions. Once in place, they form connections with existing cells and are incorporated into the circuitry.

Dr. Belluscio, who studies the olfactory system, teamed up with Heather Cameron, Ph.D., a neurogenesis researcher at the NIH’s National Institute of Mental Health, to better understand how the continuous addition of new neurons influences the circuit organization of the olfactory bulb. Using two types of specially engineered mice, they were able to specifically target and eliminate the stem cells that give rise to these new neurons in adults, while leaving other olfactory bulb cells intact. This level of specificity had not been achieved previously.    

In the first set of mouse experiments, Dr. Belluscio’s team first disrupted the organization of olfactory bulb circuits by temporarily plugging a nostril in the animals, to block olfactory sensory information from entering the brain. His lab previously showed that this form of sensory deprivation causes certain projections within the olfactory bulb to dramatically spread out and lose the precise pattern of connections that show under normal conditions. These studies also showed that this widespread disrupted circuitry could re-organize itself and restore its original precision once the sensory deprivation was reversed.

However, in the current study, Dr. Belluscio’s lab reveals that once the nose is unblocked, if new neurons are prevented from forming and entering the olfactory bulb, the circuits remain in disarray. “We found that without the introduction of the new neurons, the system could not recover from its disrupted state,” said Dr. Belluscio.

To further explore this idea, his team also eliminated the formation of adult-born neurons in mice that did not experience sensory deprivation. They found that the olfactory bulb organization began to break down, resembling the pattern seen in animals blocked from receiving sensory information from the nose. And they observed a relationship between the extent of stem cell loss and amount of circuitry disruption, indicating that a greater loss of stem cells led to a larger degree of disorganization in the olfactory bulb.

According to Dr. Belluscio, it is generally assumed that the circuits of the adult brain are quite stable and that introducing new neurons alters the existing circuitry, causing it to re-organize. “However, in this case, the circuitry appears to be inherently unstable requiring a constant supply of new neurons not only to recover its organization following disruption but also to maintain or stabilize its mature structure. It’s actually quite amazing that despite the continuous replacement of cells within this olfactory bulb circuit, under normal circumstances its organization does not change,” he said.

Dr. Belluscio and his colleagues speculate that new neurons in the olfactory bulb may be important to maintain or accommodate the activity-dependent changes in the system, which could help animals adapt to a constantly varying environment.

“It’s very exciting to find that new neurons affect the precise connections between neurons in the olfactory bulb. Because new neurons throughout the brain share many features, it seems likely that neurogenesis in other regions, such as the hippocampus, which is involved in memory, also produce similar changes in connectivity,” said Dr. Cameron.

The underlying basis of the connection between neurological disease and changes in the olfactory system is also unknown but may come from a better understanding of how the sense of smell works. “This is an exciting area of science,” said Dr. Belluscio, “I believe the olfactory system is very sensitive to changes in neural activity and given its connection to other brain regions, it could lend insight into the relationship between olfactory loss and many brain disorders.”

Novel culture system replicates course of Alzheimer’s disease, confirms amyloid hypothesis

An innovative laboratory culture system has succeeded, for the first time, in reproducing the full course of events underlying the development of Alzheimer’s disease. Using the system they developed, investigators from the Genetics and Aging Research Unit at Massachusetts General Hospital (MGH) now provide the first clear evidence supporting the hypothesis that deposition of beta-amyloid plaques in the brain is the first step in a cascade leading to the devastating neurodegenerative disease. They also identify the essential role in that process of an enzyme, inhibition of which could be a therapeutic target.

"Originally put forth in the mid-1980s, the amyloid hypothesis maintained that beta-amyloid deposits in the brain set off all subsequent events – the neurofibrillary tangles that choke the insides of neurons, neuronal cell death, and inflammation leading to a vicious cycle of massive cell death," says Rudolph Tanzi, PhD, director of the MGH Genetics and Aging Research Unit and co-senior author of the report receiving advance online publication in Nature. “One of the biggest questions since then has been whether beta-amyloid actually triggers the formation of the tangles that kill neurons. In this new system that we call ‘Alzheimer’s-in-a-dish,’ we’ve been able to show for the first time that amyloid deposition is sufficient to lead to tangles and subsequent cell death.”

While the mouse models of Alzheimer’s disease that express the gene variants causing the inherited early-onset form of the disease do develop amyloid plaques in their brains and memory deficits, the neurofibrillary tangles that cause most of the damage do not appear. Other models succeed in producing tangles but not plaques. Cultured neurons from human patients with Alzheimer’s exhibit elevated levels of the toxic form of amyloid found in plaques and the abnormal version of the tau protein that makes up tangles, but not actual plaques and tangles.

Genetics and Aging Research Unit investigator Doo Yeon Kim, PhD, co-senior author of the Nature paper, realized that the liquid two-dimensional systems usually used to grow cultured cells poorly represent the gelatinous three-dimensional environment within the brain. Instead the MGH team used a gel-based, three-dimensional culture system to grow human neural stem cells that carried variants in two genes – the amyloid precursor protein and presenilin 1 – known to underlie early-onset familial Alzheimer’s Disease (FAD). Both of those genes were co-discovered in Tanzi’s laboratory.

After growing for six weeks, the FAD-variant cells were found to have significant increases in both the typical form of beta-amyloid and the toxic form associated with Alzheimer’s. The variant cells also contained the neurofibrillary tangles that choke the inside of nerve cells causing cell death. Blocking steps known to be essential for the formation of amyloid plaques also prevented the formation of the tangles, confirming amyloid’s role in initiating the process. The version of tau found in tangles is characterized by the presence of excess phosphate molecules, and when the team investigated possible ways of blocking tau production, they found that inhibiting the action of an enzyme called GSK3-beta – known to phosphorylate tau in human neurons – prevented the formation of tau aggregates and tangles even in the presence of abundant beta-amyloid and amyloid plaques

"This new system – which can be adapted to other neurodegenerative disorders – should revolutionize drug discovery in terms of speed, costs and physiologic relevance to disease," says Tanzi. "Testing drugs in mouse models that typically have brain deposits of either plaques or tangles, but not both, takes more than a year and is very costly. With our three-dimensional model that recapitulates both plaques and tangles, we now can screen hundreds of thousands of drugs in a matter of months without using animals in a system that is considerably more relevant to the events occurring in the brains of Alzheimer’s patients."

Autism as a disorder of prediction

Autism is characterized by many different symptoms: difficulty interacting with others, repetitive behaviors, and hypersensitivity to sound and other stimuli. MIT neuroscientists have put forth a new hypothesis that accounts for these behaviors and may provide a neurological foundation for many of the disparate features of the disorder.

The researchers suggest that autism may be rooted in an impaired ability to predict events and other people’s actions. From the perspective of the autistic child, the world appears to be a “magical” rather than an orderly place, because events seem to occur randomly and unpredictably. In this view, autism symptoms such as repetitive behavior, and an insistence on a highly structured environment, are coping strategies to help deal with this unpredictable world.

The researchers hope that this unifying theory, if validated, could offer new strategies for treating autism.

“At the moment, the treatments that have been developed are driven by the end symptoms. We’re suggesting that the deeper problem is a predictive impairment problem, so we should directly address that ability,” says Pawan Sinha, an MIT professor of brain and cognitive sciences and the lead author of a paper describing the hypothesis in the Proceedings of the National Academy of Sciences this week.

“I don’t know what techniques would be most effective for improving predictive skills, but it would at least argue for the target of a therapy being predictive skills rather than other manifestations of autism,” he adds.

The paper’s senior author is Richard Held, a professor emeritus in the Department of Brain and Cognitive Sciences. Other authors are research affiliates Margaret Kjelgaard and Sidney Diamond, postdoc Tapan Gandhi, technical associates Kleovoulos Tsourides and Annie Cardinaux, and research scientist Dimitrios Pantazis.

Dealing with an unpredictable world

Sinha and his colleagues first began thinking about prediction skills as a possible underpinning for autism based on reports from parents that their autistic children insist on a very controlled, predictable environment.

“The need for sameness is one of the most uniform characteristics of autism,” Sinha says. “It’s a short step away from that description to think that the need for sameness is another way of saying that the child with autism needs a very predictable setting.”

Most people can routinely estimate the probabilities of certain events, such as other people’s likely behavior, or the trajectory of a ball in flight. The MIT team began to think that autistic children may not have the same computational abilities when it comes to prediction.

This hypothesized deficit could produce several of the most common autism symptoms. For example, repetitive behaviors and insistence on rigid structure have been shown to soothe anxiety produced by unpredictability, even in individuals without autism.

“These may be proactive attempts on the part of the person to try to impose some structure on an environment that otherwise seems chaotic,” Sinha says.

Impaired prediction skills would also help to explain why autistic children are often hypersensitive to sensory stimuli. Most people are able to become used to ongoing sensory stimuli such as background noises, because they can predict that the noise or other stimulus will probably continue, but autistic children have much more trouble habituating.

“If we were unable to habituate to stimuli, then the world would become overwhelming very quickly. It’s like you can’t escape this cacophony that’s falling on your ears or that you’re observing,” Sinha says.

Autistic children also often have a reduced ability to understand another person’s thoughts, feelings, and motivations — a skill known as “theory of mind.” The MIT team believes this could result from an inability to predict another person’s behavior based on past interactions. People with autism have difficulty using this type of context, and tend to interpret behavior based only on what is happening in that very moment. 

Leonard Rappaport, chief of the division of developmental medicine at Boston Children’s Hospital, says he believes the new theory is “a uniting concept that could lead us to new approaches to understanding the etiology and perhaps lead to completely new treatment paradigms for this complex disorder.”

“This is not the first theory to explain the complex of symptoms we see every day in our clinical programs, but it seems to explain more of what we see than other theories that explain individual symptoms,” says Rappaport, who was not involved in the research.

Timing is everything

The researchers believe that different children may show different symptoms of autism based on the timing of the predictive impairment.

“In the millisecond range, you would expect to have more of an impairment in language,” Sinha says. “In the tens of milliseconds range, it might be more of a motor impairment, and in the range of seconds, you would expect to see more of a social and planning impairment.”

The hypothesis also predicts that some cognitive skills — those based more on rules than on prediction — should remain unharmed, or even be enhanced, in autistic individuals. This includes tasks such as math, drawing, and music, which are often strengths for autistic children.

A few previous studies have tried to pinpoint which parts of the brain are involved in making predictions. So far, the strongest candidates are the basal ganglia, the nucleus accumbens, and the cerebellum — structures that are often structurally abnormal in autistic patients. “It’s a very tentative connection at the moment, but I think this is a fruitful line of inquiry for the future,” Sinha says.

Sinha’s team has already begun testing some elements of the prediction-deficit hypothesis. Initial results of one study suggest that autistic children do have an impairment in habituation to sensory stimuli; in another set of experiments, the researchers are testing autistic children’s ability to track moving objects, such as a ball. “The hypothesis is guiding us toward very concrete studies,” Sinha says. “We hope to enlist the participation of families and children touched by autism to help put the theory through its paces.”

Study finds link between neural stem cell overgrowth and autism-like behavior in mice

People with autism spectrum disorder often experience a period of accelerated brain growth after birth. No one knows why, or whether the change is linked to any specific behavioral changes.

A new study by UCLA researchers demonstrates how, in pregnant mice, inflammation, a first line defense of the immune system, can trigger an excessive division of neural stem cells that can cause “overgrowth” in the offspring’s brain.

The paper appears Oct. 9 in the online edition of the journal Stem Cell Reports. 

“We have now shown that one way maternal inflammation could result in larger brains and, ultimately, autistic behavior, is through the activation of the neural stem cells that reside in the brain of all developing and adult mammals,” said Dr. Harley Kornblum, the paper’s senior author and a director of the Neural Stem Cell Research Center at UCLA’s Semel Institute for Neuroscience and Human Behavior.

In the study, the researchers mimicked environmental factors that could activate the immune system — such as an infection or an autoimmune disorder — by injecting a pregnant mouse with a very low dose of lipopolysaccharide, a toxin found in E. coli bacteria. The researchers discovered the toxin caused an excessive production of neural stem cells and enlarged the offspring’s’ brains.

Neural stem cells become the major types of cells in the brain, including the neurons that process and transmit information and the glial cells that support and protect them.

Notably, the researchers found that mice with enlarged brains also displayed behaviors like those associated with autism in humans. For example, they were less likely to vocalize when they were separated from their mother as pups, were less likely to show interest in interacting with other mice, showed increased levels of anxiety and were more likely to engage in repetitive behaviors like excessive grooming.

Kornblum, who also is a professor of psychiatry, pharmacology and pediatrics at the David Geffen School of Medicine at UCLA, said there are many environmental factors that can activate a pregnant woman’s immune system.

“Although it’s known that maternal inflammation is a risk factor for some neurodevelopmental disorders such as autism, it’s not thought to directly cause them,” he said. He noted that autism is clearly a highly heritable disorder, but other, non-genetic factors clearly play a role.

The researchers also found evidence that the brain growth triggered by the immune reaction was even greater in mice with a specific genetic mutation — a lack of one copy of a tumor suppressor gene called phosphatase and tensin homolog, or PTEN. The PTEN protein normally helps prevent cells from growing and dividing too rapidly. In humans, having an abnormal version of the PTEN gene leads to very large head size or macrocephaly, a condition that also is associated with a high risk for autism.

“Autism is a complex group of disorders, with a variety of causes,” Kornblum said. “Our study shows a potential way that maternal inflammation could be one of those contributing factors, even if it is not solely responsible, through interactions with known risk factors.”

In addition, the team found that the proliferation of neural stem cell and brain overgrowth was stimulated by the activation of a specific molecular pathway. (A pathway is a series of actions among molecules within a cell that leads to a certain cell function.) This pathway involved the enzyme NADPH oxidase, which the UCLA researchers have previously found to be associated with neural stem cell growth.

“The discovery of these mechanisms has identified new therapeutic targets for common autism-associated risk factors,” said Janel Le Belle, an associate researcher in Kornblum’s lab and the paper’s lead author. “The molecular pathways that are involved in these processes are ones that can be manipulated and possibly even reversed pharmacologically.

“In agreement with past clinical findings, these data add to the significant evidence that autism-associated brain alterations begin prenatally and continue to evolve after birth,” she said.

Kornblum added that the findings that neural stem cell hyper-proliferation can contribute to autism-associated features may be somewhat surprising. “Autism neuropathology is primarily thought of as a dysregulation of neuronal connectivity, although the molecular and cellular means by which this occurs is not known,” he said. “Therefore, our hypothesis — that one potential means by which autism may develop is through an overproduction of cells in the brain, which then results in altered connectivity — is a new way of thinking about autism etiology.”

The next step, the researchers say, is to determine if and how the changes they observed lead to changes in the connections between brain cells, and if those effects can be altered after they have happened.

An enzyme and synaptic plasticity: Study reveals novel role for the Pin1

Synapses are “dynamic” things: they can regulate their action in neural processes related to learning, for example, but also as a consequence of diseases. A research team –led by SISSA– has demonstrated the role of a small enzyme (Pin1) in synaptic plasticity. The study has just been published in the journal Nature Communications.

A small, “empty” space teeming with activity: a synapse is a complex structure where the neural (electrical) signal from the presynaptic neuron, as it travels towards its target –a muscle, a gland or another neuron– turns into a chemical signal capable of crossing the synaptic space before becoming electrical again once on the other side. A synapse is a “dynamic” space not only because of the endless work that goes on there, but also for its ability to change its action over time (synaptic plasticity) as a result of either normal physiological processes (e.g., during learning) or because of disorders due to pathological conditions. A study, mainly carried out by SISSA researchers (which also involved the University of Zurich, LNCIB in Trieste, and EBRI in Rome), showed that a small enzyme (Pin1, peptidylprolyl isomerase) that plays a mediating role in signal transmission has an effect on synaptic plasticity.

The synapse we studied is of the inhibitory kind. The signal it transmits hinders activation of the postsynaptic neuron, making it less likely for it to become activated and emit its action potential”, explains Paola Zacchi, a SISSA researcher who coordinated the study. “When Pin1 is absent from the synapse, signal transmission occurs “at full strength”, but also without control. Instead, when it is present, it regulates signal strength, making it weaker. We observed that Pin1 is able to modify the number of postsynaptic receptors”. The larger the number of receptors capable of binding to the neurotransmitter, the stronger the signal that reaches the postsynaptic membrane. “This also means that Pin1 plays a role in plasticity” explains Zacchi.

How does a synapse work? “A chemical synapse, the most common in vertebrates, is a small gap between nerve cells where the passage of a neural signal occurs”, explains Zacchi. In chemical synapses the two neurons are not in contact but they are separated by a distance of about 20 nanometres. For this reason, the electrical signal travelling along the presynaptic nerve ending is interrupted before resuming on the neuron on the other side of the gap. In between the two nerve cells the electrical signal is translated into a chemical signal (which then becomes electrical again).

“Arrival of the action potential on the presynaptic button causes release, into the interneural space, of molecules of neurotransmitter, which are picked up by receptors on the postsynaptic membrane”, says Zacchi. “If the synapse is excitatory, this leads to postsynaptic activation which, if sufficiently intense, triggers another action potential. If the synapse is inhibitory, as in our studies, the signal suppresses postsynaptic activation and inhibits firing of the electrical potential. In the process of neurotransmitter release and binding, other molecules come into play, such as scaffold proteins, which assemble receptors at the right place on the membrane in front of the neurotransmitter release sites, and neuroligins which act as bridges between the two ends of the synapse as well as interacting with the scaffold proteins. Pin1, the enzyme in the study, interacts with both neuroligins and scaffold proteins.

The Pin1 enzyme has long been known for its role in cancer and the development of neurodegenerative diseases such as Alzheimer’s and Parkinson’s (whereas neuroligins seem to be involved in autism). “Studies like this enhance our understanding of the biochemical mechanisms of synaptic plasticity, extending our knowledge of healthy mechanisms, but also helping those who are trying to understand what can be done in a wide range of pathological conditions”.

Smoking cannabis doesn’t make you more creative

People often think that smoking cannabis makes them more creative. However, research by Leiden psychologists Lorenza Colzato and Mikael Kowal shows that the opposite is true. They published their findings on 7 October in Psychopharmacology.

Strong cannabis doesn’t work

The findings show that cannabis with a high concentration of the psychoactive ingredient THC does not improve creativity. Smokers who ingested a low dose of THC, or none at all (they were given a placebo), performed best in the thinking tasks that the test candidates had to carry out.  A high dose of THC was actually shown to have a negative effect on the ability to quickly come up with as many solutions as possible to a given problem.

Increased creativity is an illusion

The research findings contradict the claims of people who say that their thinking changes and becomes more original after smoking a joint. There’s no sign of any increased creativity in their actual performance, according to Colzato. ‘The improved creativity that they believe they experience is an illusion.’

Too much dope is counterproductive

Colzato: ‘If you want to overcome writer’s block or any other creative gap, lighting up a joint isn’t the best solution. Smoking several joints one after the other can even be counterproductive to creative thinking.’  

The research method

Colzato and her PhD candidate Kowal were the first researchers to study the effects of cannabis use on creative thinking. For ethical reasons, only cannabis users were selected for this study. The test candidates were divided into three groups of 18. One group was given cannabis with a high THC content (22 mg), the second group was given a low dose (5.5 mg) and the third group was given a placebo. The high dose was equivalent to three joints and the low dose was equal to a single joint. Obviously, none of the test candidates knew what they were being given; the cannabis was administered via a vaporizer. The test candidates then had to carry out cognitive tasks that were testing for two types of creative thinking: 

• Divergent thinking: generating rapid solutions for a given problem, such as: “Think of as many uses as you can for a pen?”
• Convergent thinking: Finding the only right answer to a question, such as: “What is the link between the words ‘time’, ‘hair’ and ‘stretching’.  (The answer is ‘long’.)

Similar but different: new discovery for degenerative disease