A new study in the October 31st issue of Cell, a Cell Press journal, has revealed the molecular and cellular underpinnings of one of the most common, single gene causes for learning disability in humans.  The findings made in learning disabled mice offer new insight into what happens in the brain when we learn and remember.

While most previous studies have focused on the role of brain cells that excite other brain cells in the process of learning, the current results suggest that inhibitory neurons and a careful balance between excitatory and inhibitory signals may be just as essential, according to the researchers.  They liken the role of those inhibitory and excitatory signals in the brain to the role of red and green stoplights in directing traffic.

” The significance of these findings is two-fold,” said Alcino Silva of the University of California, Los Angeles.  “First, we have in great detail the exact mechanism for one of the most common single gene causes for learning disability known.  It’s also a beachhead in our understanding of the balance between excitation and inhibition critical for learning.”

Learning disabilities are estimated to affect one in five people worldwide.  “It’s a huge problem and there is little known about their causes,” Silva said.

To begin to chip away at those underlying causes for conditions that often have complex causes, Silva’s team began a hunt several years ago to unravel the mechanisms responsible for a couple of single gene disorders that lead to learning disability.

In the new study, they examined mice with learning disabilities resulting from a condition called neurofibromatosis type 1.  The condition stems from a defect in the Nf1 gene encoding a protein called neurofibromin.  Earlier studies showed that neurofibromin controls a “Ras/Erk” signal that is involved in long-term potentiation (LTP) and learning in mice.  LTP is a process that strengthens the connections between neurons in the brain–the cellular basis for learning and memory.

Now, the researchers have found that the deficits in spatial learning experienced by mice with an abnormal version of the Nf1 gene stem from an increased release by inhibitory neurons of a chemical nerve messenger (or neurotransmitter) called GABA.  GABA is the chief inhibitory neurotransmitter in the central nervous systems of mammals.

That rise in GABA leads to deficits in the plasticity of neurons required for learning and memory.  Importantly, they also show that the learning deficits in the mice can be reversed with treatments that reign GABA levels back in.  They also show that GABA levels normally swell when mice learn, suggesting that a balance of GABA is the key.

Silva’s team notes another recent study implicating changes in GABA inhibition in the learning deficits exhibited by an animal model of Down’s syndrome.  Although learning disability—characterized by profound changes in one part of brain function—differs widely from mental retardation, that finding together with the new study suggest there may nevertheless be a common thread, Silva said.

Ultimately, these insights could lead to new ways to treat learning disabilities, although reaching that goal won’t be a simple proposition.

” It won’t be a single step from the mechanism to finding a drug,” Silva said.  As with other complex disorders like cancer, he said, it will likely take years of exploration to turn scientific advances into medical applications.  Nevertheless, “the more insight we have into the mechanisms responsible, the more likely it is that our treatment efforts will be effective.  ”

The new study is also representative of the exciting advances in the study of neuroscience more broadly.

” We are at the beginning of a wonderful journey into how the human mind works,” Silva said.  “We are developing a highly detailed view of what goes on in the brain when we learn and remember.  There is nothing more inspiring; it’s what makes us who we are.”

Providing preventive treatment for malaria, given once per term, dramatically reduces rates of malaria infection and anaemia among schoolchildren, and significantly improves their cognitive ability, according to new research published today in the Lancet.

Malaria is a major cause of morbidity and mortality in early childhood, but its consequences during the school-age years are less widely acknowledged.  By the time an African child enters school they have generally been repeatedly infected with malaria and have acquired immunity to the parasite making them less likely to die.  However, malaria still accounts for up to 20% of deaths among schoolchildren, is an important cause of school absenteeism, and may hinder educational achievement.  Additionally, many schoolchildren continue to harbour malaria parasites without displaying any symptoms of disease.  These asymptomatic infections frequently go unrecognised and untreated, leading to anaemia and, as demonstrated for the first time in this study, impaired performance in school.

School-based health programs have been shown to work well in combating other diseases, such as worm infections, but less is known about their role in tackling malaria.  Yet more children are now attending school than ever before and governments are increasingly recognising the importance of child health for educational achievement.

A multi-disciplinary team of Kenyan and British researchers investigated the impact of IPT, a new method of tackling malaria which involves the mass administration of a full course of an anti-malarial drug irrespective of whether children are infected.  They assessed whether IPT could reduce the prevalence of anaemia, and improve classroom attention and educational achievement in schoolchildren.  They carried out a randomised, placebo-controlled trial of IPT in 30 primary schools in a rural area of high malaria transmission in western Kenya.  In total, 4916 children, aged 5-18 years, received three treatments (sulfadoxine-pyrimethamine combined with amodiaquine, or a dual placebo) at four-monthly intervals, once each school term.  The impact of treatment was assessed through cross-sectional surveys 12 months later.

IPT dramatically reduced the occurrence of malaria infection in schoolchildren.  The risk of anaemia was halved among those receiving IPT compared with the controls, and significant improvements were also seen in class-based tests of sustained attention among those receiving IPT.  No impact was observed for educational achievement.

Dr. Matthew Jukes, Assistant Professor of International Education at the Harvard Graduate School of Education, worked on the study and comments: ‘Although it has long been suspected that malaria impairs school performance, this is the first study to provide evidence of a direct link between malaria and reduced attention in class.  These results indicate that malaria infection may hinder learning and its prevention could be important to enhance the educational potential of schoolchildren.’

Dr. Siân Clarke, a Lecturer in Malaria Research and Control at the London School of Hygiene & Tropical Medicine, comments: ‘Our findings highlight the neglected burden of malaria in older children, and reveal that malaria infection in schoolchildren may have more profound consequences than previously appreciated.  Preventing malaria could have important health and cognitive benefits for African schoolchildren and deserves more attention.  These results show us that intermittent preventive treatment in schools is a novel and effective means to address this problem.’

The findings of the study have particular relevance for the global ‘Education for All’ initiative which aims to achieve universal school enrolment and enhance schooling.

The intervention could prove a valuable and affordable addition to realising ‘Education for All’ goals through school health and nutrition programmes which already provide treatments against worm infections.  School-age children represent 26% of Africa’s population where 94% of children go to school.  Numerically, this represents up to191 million children who could benefit from a systematic approach to school-based malaria control, which could include IPT.

Dr. Simon Brooker, a Reader in Tropical Epidemiology at the London School of Hygiene & Tropical Medicine adds: ‘For a small financial investment the potential gains from the approach of IPT are extremely attractive.  An important next step will be to work with government and development partners in Africa to investigate further the feasibility and costeffectiveness of scaling up an IPT package within the context of school health programmes’.

Research involving large Middle Eastern families, sophisticated genetic analysis and groundbreaking neuroscience has implicated a half-dozen new genes in autism.  More importantly, it strongly supports the emerging idea that autism stems from disruptions in the brain’s ability to form new connections in response to experience – consistent with autism’s onset during the first year of life, when many of these connections are normally made.

Interestingly, not all the affected genes were actually deleted, but only prevented from turning on – offering hope that therapies could be developed to reactivate the genes.  The study, led by researchers at Children’s Hospital Boston and members of the Boston-based Autism Consortium, is the cover article in the July 11 issue of Science.

Autism genes have been difficult to identify because the disorder is complex, with a variety of causes stemming from many possible genes or combinations of genes.  In addition, since people with autism tend not to have children, most of the genes identified thus far aren’t inherited from a parent, but instead are mutated during embryonic development, making them hard to track through traditional linkage studies in families.

Christopher Walsh, MD, PhD, chief of genetics at Children’s Hospital Boston, approached the problem by studying Middle Eastern families.  In traditional Arab societies, it is common for cousins to marry, increasing the likelihood that offspring will inherit rare mutations.  Middle Eastern families also tend to have many children, making them ideal for mapping genes.

“To map a gene for autism in American families, averaging two to three kids per family, you would need to pool many families,” says Walsh, who is also a Howard Hughes Medical Institute investigator at Beth Israel Deaconess Medical Center (BIDMC).  “In larger families, one family alone may be enough to definitively localize a gene.”

The Homozygosity Mapping Collaborative for Autism (HMCA) recruited 104 families with a high incidence of autism from the Arabic Middle East, Turkey and Pakistan; 88 of these families have cousin marriages.  Local clinicians were rigorously trained in administering standardized autism research assessments.  Walsh’s team later flew to sites in Turkey, Dubai, Kuwait and Saudi Arabia to confirm the diagnoses.

Using a technique called homozygosity mapping Walsh and colleagues compared the DNA of family members with and without autism, searching for recessive mutations—those that cause disease only when a child inherits two copies.

“We check each set of chromosomes from beginning to end, looking for one place where the child has two identical pieces of DNA on both chromosomes,” Walsh explains.  “Eventually we find a spot where all affected children have two identical chunks of DNA, and where unaffected children have something different.”

Just over 6 percent of the 88 families showed rare, inherited deletions within DNA regions linked to autism.  These affected DNA regions varied among families, further indication of autism’s large variety of genetic causes.  In all, the technique identified five chromosome deletions affecting at least six identifiable genes (C3orf58, NHE9, PCDH10, contactin-3 [CNTN3], RNF8, and genes encoding a cluster of cellular sodium channels).

One of the genes, NHE9, was also found to be mutated in European and American children with autism (particularly those with both autism and seizures).

Experience-dependent learning: A common thread

The genes discovered are diverse in function, but all seem to be part of a fundamental molecular network that orchestrates the refinement and maturation of brain connections, or synapses, in response to input from the outside world.  It is the refinement of these synaptic connections that is the basis of learning and memory, suggesting that autism at its heart may represent molecular defects of learning.

“This network can be disrupted in a myriad of ways, and may be one mechanism that people with a variety of autism-linked mutations share,” says Michael Greenberg, PhD, a coauthor on the paper and director of the Neurobiology Program at Children’s Hospital Boston.

Normally, as a neuron (brain cell) receives an incoming message at the synapse, a network of reactions is sparked that extends all the way to its nucleus.  Greenberg and his colleagues had long been mapping this network, and had previously found that it activates at least 300 genes.  These genes then communicate back to the neuron’s surface, telling the cell to make a new synapse, strengthen the synapse that’s already there, eliminate a synapse, or make a different kind of synapse.  This give-and-take system is how the brain builds its circuitry; neuroscientists call it “experience-dependent learning.”

Working independently of Walsh, Greenberg and his colleagues had already identified three of the same genes found in the Middle Eastern patients (c3orf58, NHE9, and PCDH10) while looking for genes that turn on or off in neurons as part of this network – either in response to synaptic activity or through so-called transcription factors that are activated by synaptic activity.

The work bolsters a growing body of evidence that autism may represent a disruption of the brain’s ability to modify its synaptic connections in response to experience.

“Taken together, our findings suggest that experience-dependent learning could be relevant to autism, and that autism might result from the deregulation of any one of a number of genes that are part of the same signaling pathway,” Greenberg says.

Can normal function be revived?

Interestingly, only one chromosome deletion found in the Middle Eastern families actually removed a gene – in most cases, what was lost was a region adjacent to the gene that contains its “on/off” switches.  This has important implications for therapy, because it suggests that autism mutations don’t always remove a gene altogether, but only inhibit its activity in certain contexts, says Eric Morrow, MD, PhD, of Massachusetts General Hospital, who is co-first author of the paper with Seung-Yun Yoo, PhD.  “This means that we would not need to replace the gene, if we could only figure out how to reactivate it, perhaps with medications,” says Morrow, who also holds appointments at BIDMC and Children’s.

The findings also support the use of behavioral therapies in autism, which expose children to a rich environment and highly repetitive activities that may help turn on the genes and strengthen synaptic connections, Morrow adds.

“This publication a big event in the world of autism research,” says Clarence Schutt, PhD, Scientific Advisor to the Nancy Lurie Marks Family Foundation, which funded work by both the Walsh and Greenberg labs.  “To have discovered a connection between autism and activity-related gene expression at the synapse will put this field at the center of neuroscience.”

Many of the seemingly disparate mutations recently discovered in autism may share common underlying mechanisms, say researchers supported in part by the National Institute of Mental Health (NIMH), a part of the National Institutes of Health (NIH).  The mutations may disrupt specific genes that are vital to the developing brain, and which are turned on and off by experience-triggered neuronal activity.

A research team led by Christopher Walsh, M.D., Ph.D., and Eric Morrow, M.D., Ph.D., of Harvard University, found two large sections missing on chromosomes in people with autism and traced them to likely inherited mutations in such genes regulated by neuronal activity.  They report their findings in the July 11, 2008 issue of Science.  The study was also supported in part by the NIH’s National Center for Research Resources, National Human Genome Research Institute, Eunice Kennedy Shriver National Institute of Child and Human Development, and the National Institute on Neurological Disorders and Stroke.

The study breaks new ground for complex disorders like autism, taking advantage of a shortcut to genetic discovery by sampling families in which parents are cousins.  The researchers found genes and mutations associated with autism in 88 families from the Middle East, Turkey and Pakistan in which cousins married and had children with the disorder.

“The emerging picture of the genetics of autism is quite surprising.  There appear to be many separate mutations involved, with each family having a different genetic cause,” explained NIMH Director Thomas R. Insel, M.D. “The one unifying observation from this new report is that all of the relevant mutations could disrupt the formation of vital neural connections during a critical period when experience is shaping the developing brain.”

Earlier studies had suggested that the individually rare mutations are present in at least 10 percent of sporadic cases of autism, which is the most common form.

The researchers used a technique that pinpoints from a relatively small group of families genes responsible for disorders that can be amplified by parenthood among relatives, which can increase transmission of recessive diseases.  Evidence had hinted at such transmission in autism, and the large amount of genetic information obtainable from such families reduced the need for a much larger sample including many families with multiple affected members.

The ratio of females to males with autism – normally one female to four males – was less lopsided in such families in which parents share a common recent ancestor.  This ratio equalized even more in a subset of these families with more than one affected member, suggesting a doubling of the rate of autism, due to recessive causes on non-sex-linked chromosomes.  Also, autism-linked spontaneous deletions and duplications of genetic material were relatively uncommon in these families, suggesting recessive inherited causes.

The researchers found multiple different genetic causes of autism in different individuals with little overlap between the families in which parents shared ancestry.  Yet a few large inherited autism-linked deletions, likely mutations, in a minority of families stood out.  The largest turned out to be in or near genes regulated, directly or indirectly, by neuronal activity.

“Autism symptoms emerge at an age when the developing brain is refining the connections between neurons in response to a child’s experience,” explained Walsh.  “Whether or not certain important genes turn on is thus dependent on experience-triggered neural activity.  Disruption of this refinement process may be a common mechanism of autism-associated mutations.”

Neuroscientists at Georgetown University Medical Center have solved a mystery that lies at the heart of human learning, and they say the solution may help explain some forms of mental retardation as well as provide clues to overall brain functioning.

Researchers have long puzzled over why a gene known as brain-derived neurotrophic factor (BDNF), which is crucial to the ability of neurons in the hippocampus to grow and connect to each other – forming the basis of memory and learning – produces two different transcripts, which then each fabricate identical proteins.

In the July 11 issue of Cell, the scientists report the answer, and it has to do with transportation.  They found that the longer of the two transcripts (messenger RNAs, or mRNAs) include extra sequences that “motor” molecules attach to, in order to move the information far away from the nucleus of the cell and toward the long, tree-like branches of the nerve cell known as dendrites.  There, protein-synthesizing machines use that mRNA to produce protein that helps small protrusions (called dendritic spines) on these dendrites grow.

The shorter of the mRNAs are also moved from the nucleus into the cytoplasm of the neuron, but they do not need to be transported to dendrites.  These transcripts produce an identical protein, but in this case, investigators believe they help the axon, the long cable-like body of a neuron, grow.

Learning occurs when both axons and dendritic spines grow and touch each other, forming connections, and existing connections are strengthened.  The scientists’ findings provide a critical understanding of how dendritic spines grow and mature, but this understanding may be more broadly applied.

That’s because as exciting as the findings are for understanding the function – and dysfunction of BDNF as it relates to human learning, they also are relevant for other genes and proteins, says the study’s lead investigator, Baoji Xu, Ph.D., an assistant professor in the Department of Pharmacology at Georgetown.

“The fascinating thing is that many genes produce multiple transcripts for the same protein – and no one has known why,” he says.  “So what we found here is likely very applicable to other genes.  It reveals a mechanism for differential regulation of subcellular functions of proteins.”

In this study, Xu and his research team, which included investigators from the National Institute of Child Health and Human Development (NICHHD), Emory University, and the University of Colorado, looked at why a neuron needs two “species” of BDNF mRNAs.

The gene produces a growth factor that makes neurons grow, and is vital to initial development of the brain; mice born without BDNF have developmental deficits and soon die.  BDNF is also secreted by neurons in adult brains when needed, and that is usually when synaptic junctions between neurons require strengthening, a condition known as “synaptic plasticity” that underlies memory and learning.  “If BDNF is deleted in an adult animal’s brain, the animal will struggle to learn new tasks,” Xu says.

Scientists had found that protein translation occurs in dendrites, and they believed that this protein production was important for synaptic plasticity, “but it has been difficult to study local protein synthesis only in dendrites,” Xu says.  “When you change protein synthesis in dendrites, you also affect protein production in other parts of the neuron.”

To solve that problem, Xu and the scientists managed to create mouse mutants in which the long BDNF mRNA variant is converted to the shorter mRNA form.  They found that in these mice, dendritic spines form normally, but do not mature properly and aren’t “pruned” as they need to be.  “This process is important for the normal function of the brain.  Without it, the mice can’t refine neuronal connections in response to learning,” he says.

Some people diagnosed with mental retardation suffer from the same problem, Xu adds.  “At a certain stage of development, maturation of dendritic spines is frozen.  For example, in Fragile X Syndrome, there are too many immature dendritic spines.

“What we see in our mutant mouse and in Fragile X is similar,” he says.  “If we could find a way to increase BDNF synthesis in dendrites, it may be helpful to people with mental retardation.

“That, of course, is just a theory, but now that we understand the function of these two different mRNAs, we can begin to explore what issues their dysfunction causes in humans,” Xu says.

A study from researchers at Children’s Hospital Boston published in Pediatrics found that a simple infection control intervention in elementary schools – disinfecting frequently-touched surfaces and using alcohol-based hand sanitizers – helped reduce illness-related student absenteeism.Illnesses caused by bacteria and viruses account for millions of lost school days each year.(1) According to Thomas Sandora, MD, MPH, a pediatric infectious diseases specialist at Children’s Hospital Boston, “The best ways to avoid common infections are cleaning your hands and preventing exposure to the germs that cause these illnesses. Our research indicates that elementary schools should consider a few simple infection control practices to help keep students healthier.”

The study, led by Dr. Sandora, was a randomized, controlled trial involving 285 third-, fourth-, and fifth-grade students in an elementary school system in Avon, Ohio. Teachers in intervention classrooms used disinfecting wipes on student desks, and students used hand sanitizer in the classroom at key points throughout the school day. Control classrooms followed usual hand washing and cleaning procedures.

Over eight weeks, researchers tracked the frequency of absences and the reasons for missing school. Study investigators also tested several classroom surfaces for total bacterial counts and for the presence of several common viruses.

Researchers found absenteeism rates for gastrointestinal illnesses were nine percent lower in classrooms that followed the infection control regimen of disinfecting surfaces and using alcohol-based hand sanitizers. The absenteeism rate for respiratory illness was not affected by this intervention.

Gastrointestinal illnesses are extremely common for school-age children, and children can be at risk for these infections because of frequent exposure to ill peers and poor hand hygiene.(1) In fact, the bacteria and viruses that cause these gastrointestinal infections can be easily passed from one person to another on the hands.(2) The germs can also survive on surfaces in the environment, where some of them can persist for hours to days.(1)

The study suggests that schools should consider adopting simple infection control practices, including disinfecting desktops once a day and using hand sanitizer before and after lunch, to help reduce days lost to common illnesses.

The gender gap in math perceived to exist between girls and boys has long been contested. New research published in the journal Science sheds clarity on the debate and demonstrates that girls perform better in mathematics in more gender equal societies, in some cases besting male peers.The research, led in part by Kellogg School of Management Professor Paola Sapienza, sought to address the issue of whether social and cultural factors influence women’s success in math and science. Sapienza and her colleagues Luigi Guiso (Instituto Universitario Europeo) and Ferdinando Monte and Luigi Zingales (University of Chicago), empirically investigated whether a global gender gap exists in math to understand the relative importance of biology and culture on the development of basic mental attributes that are valuable for conducting math and science.

“The so-called gender gap in math skills seems to be at least partially correlated to environmental factors” says Sapienza. “The gap doesn’t exist in countries in which men and women have access to similar resources and opportunities.”

In search of bridges across the math gender gap, Sapienza and her colleagues analyzed data from more than 276,000 children in 40 countries. The large number of subjects and broad range of social systems represented were key to the validity of the study. Each child took the 2003 Organisation for Economic Co-operation and Development Programme for International Student Assessment (PISA), an internationally standardized assessment of math, reading, science and problem-solving ability.

Based on the PISA analysis, Sapienza and her colleagues determined that while the global pattern shows that boys tended to outperform girls in math (on average girls score 10.5 points lower than boys), this advantage was not always the case. In a few countries, including Iceland, Sweden and Norway, girls scored as well as boys or better.

Sapienza and colleagues examined social features that might explain the variance from country to country. The team used four tools to measure how well women were integrated into each society compared with men. These tools were the 2006 Gender Gap Index (GGI) developed by the World Economic Forum (WEF); the World Values Survey; the percentage of women aged 15 or older who are eligible to work in each country’s labor force; and the WEF political empowerment index, which measures the representation of women in government.

Sapienza’s team found that, in more gender equal societies, the gender gap in math disappears. For example, the math gender gap almost disappeared in Sweden (GGI = 0.81), while girls scored 23 points below boys in math in Turkey (GGI = 0.59). Not only did average girls’ scores improve as equality improved, but the number of girls reaching the highest levels of performance also increased.

Math and science rates for girls in the U.S., which ranks 23rd on the GGI scale with a score of 0.7, fell in the middle of the pack. On average, U.S. girls score almost 10 points lower than U.S. boys in mathematics, which is around the average for all countries analyzed in the study.

The research also found a striking gender gap in reading skills. In every country girls perform better than boys in reading In more gender equal societies, the girls’ advantage in reading over boys increases further. On average, girls have reading scores that are 32.7 points higher than those of boys (6.6 percent higher than the mean average score for boys). In Turkey, this amounts to 25.1 points higher and in Iceland, girls score 61.0 points higher.

Said Sapienza, “Our research indicates that in more gender equal societies, girls will gain an absolute advantage relative to boys.”