Category: Schizophrenia

Research comparing brain development in humans and our closest nonhuman primate relatives, chimpanzees, reveals how quickly myelin in the cerebral cortex grows, shedding light on the evolution of human cognitive development and the vulnerability of humans to psychiatric disorders. Myelin is the fatty insulation surrounding axon connections of the brain.

Recent research by Chet Sherwood, associate professor of anthropology in Columbian College of Arts and Sciences, along with Daniel Miller, a former GW graduate student, and other colleagues, reveals this key difference in brain development between human and chimpanzee. The findings were recently published in the September 24th edition Proceedings of the National Academy of Sciences (PNAS).

In the article, Dr. Sherwood and co-authors write that the development of myelin from birth to adulthood in humans is protracted in comparison to chimpanzees. In humans, myelin develops slowly during childhood, followed by a delayed period of maturity beyond adolescence and into early adulthood. In contrast, in chimpanzees, the development of myelin already starts at a relatively more mature level at birth and ceases development long before puberty.

“These observations indicate that a marked delay in the development schedule of the human neocortex may play an important role in the growth of connections that contribute to our species-specific cognitive abilities,” wrote Dr. Sherwood and co-authors.

The developmental timing of myelination is important because it establishes connectivity among parts of the growing brain, which is essential to higher-order cognitive functions, such as decision-making and emotional regulation. These cognitive functions are known to mature relatively late in humans, after the time of adolescence. Also, this period of persistent myelin development during early adulthood in humans is a time of particular vulnerability to neuropsychiatric diseases, including schizophrenia, bipolar disorder, and depression.

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Journal Reference:

1. D. J. Miller, T. Duka, C. D. Stimpson, S. J. Schapiro, W. B. Baze, M. J. McArthur, A. J. Fobbs, A. M. M. Sousa, N. Sestan, D. E. Wildman, L. Lipovich, C. W. Kuzawa, P. R. Hof, C. C. Sherwood. Prolonged myelination in human neocortical evolution. Proceedings of the National Academy of Sciences, 2012; DOI: 10.1073/pnas.1117943109

Scientists studying a rare genetic disorder have identified a molecular pathway that may play a role in schizophrenia, according to new research in the Oct. 10 issue of The Journal of Neuroscience. The findings may one day guide researchers to new treatment options for people with schizophrenia — a devastating disease that affects approximately 1 percent of the world's population.

Schizophrenia is characterized by a multitude of symptoms, including hallucinations, social withdrawal, and learning and memory deficits, which usually appear during late adolescence or early adulthood. Efforts to identify disease causes have been complicated by the fact that no single genetic mutation is strongly associated with the disease. By studying a rare genetic disorder that increases the risk of schizophrenia, Laurie Earls, PhD, and colleagues in the laboratory of Stanislav Zakharenko, MD, PhD, at St. Jude Children's Research Hospital identified molecular changes that affect memory and are also present in people with schizophrenia.

Approximately 30 percent of people with a genetic disorder known as 22q11 deletion syndrome develop schizophrenia, making it one of the strongest risk factors for the disease. In previous studies of mice with the 22q11 deletion, Zakharenko's group identified changes in nerve cells leading to deficits in the hippocampus — the brain's learning and memory center — that appear with age. In the current study, the group confirmed similar molecular changes occur in people with schizophrenia. They also zeroed in on the gene contributing to the nerve cell changes.

"This study makes some very important discoveries about the precise mechanisms underlying the learning and memory deficits seen in the genetic mouse model — problems that are a central part of the human disease," said Carrie Bearden, PhD, an expert on 22q11 deletion syndrome at the University of California, Los Angeles, who was not involved in the study. "Pinpointing the specific gene involved is the first step toward developing targeted therapies that could reverse the cognitive deficits associated with schizophrenia, both in the context of this genetic mutation and the broader population," she added.

In previous studies, Zakharenko's group found that abnormal nerve cell communication and cognitive dysfunction was associated with elevated levels of a protein that regulates calcium in certain nerve cells known as Serca2. These abnormalities are only detectable with age in mice with the 22q11 deletion.

In the current study, the researchers identified the gene Dgcr8 as the source of the changes.It produces molecules called microRNAs that normally keep Serca2 in check. Without them, the protein becomes elevated.By adding these molecules back into the hippocampus of animals with the 22q11 deletion, the researchers were able to reduce elevated Serca2 levels and reduce the cellular deficits associated with this genetic defect.

To assess whether the findings from these genetic mouse studies might translate to schizophrenia, the authors analyzed post-mortem brain tissue from people with schizophrenia. The researchers discovered that Serca2 was elevated even in patients with schizophrenia who did not have the 22q11 deletion.

"These data suggest a link between the nerve cell changes in patients with the 22q11 deletion syndrome and those that occur in patients with schizophrenia," Zakharenko said. "Serca2 regulation represents a novel therapeutic target for schizophrenia."

This study was funded by the National Institute of Mental Health and St. Jude Children's Research Hospital.

Columbia University Medical Center (CUMC) researchers have identified dozens of new spontaneous genetic mutations that play a significant role in the development of schizophrenia, adding to the growing list of genetic variants that can contribute to the disease. The study, the largest and most comprehensive of its kind, was published today in the online edition of the journal Nature Genetics.

Although schizophrenia typically onsets during adolescence and early adulthood, many of the mutations were found to affect genes with higher expression during early-to-mid fetal development. Together, the findings show that both the function of the mutated gene and when the gene is expressed are critically important in determining the risk for schizophrenia.

The findings inform epidemiologic studies showing that environmental factors, such as malnutrition or infections during pregnancy, can contribute to the development of schizophrenia. "Our findings provide a mechanism that could explain how prenatal environmental insults during the first and second trimester of pregnancy increase one's risk for schizophrenia," said study leader Maria Karayiorgou, MD, professor of psychiatry at CUMC, and acting chief, division of Psychiatric and Medical Genetics, New York State Psychiatric Institute. "Patients with these mutations were much more likely to have had behavioral abnormalities, such as phobias and anxiety in childhood, as well as worse disease outcome."

In an earlier study of 53 families, the team of investigators found that spontaneous, or de novo, mutations — genetic errors that are present in patients but not in their parents — play a role in a substantial portion of sporadic cases of schizophrenia. The mutations were found in the part of the genome that codes for proteins, known as the exome.

In the larger, current study, the researchers performed whole-exome sequencing on 231 patient "trios" from the United States and South Africa. Each trio consisted of a patient and both of his or her parents, who were unaffected by the disease. By comparing the exomes of the patients with those of their parents, the researchers were able to identify de novo rather than heritable, mutations that may contribute to schizophrenia. This is the first study of this scale to search for single nucleotide variations in the exomes of schizophrenia patients. Previous studies from the Columbia group and others searched for much larger genetic variations, such as gene deletions or duplications.

The researchers identified many mutated genes with diverse functions. They also identified four new genes (LAMA2, DPYD, TRRAP, and VPS39) affected by recurrent de novo events within or across the two populations, a finding unlikely to have occurred by chance.

The researchers estimate that several hundred loci (genetic locations) can contribute to the development of schizophrenia. "The chance that two patients have exactly the same mutation or combination of mutations is rather small" said Dr. Karayiorgou. "What is intriguing is that despite this variability, people with schizophrenia tend to have, more or less, the same phenotype — that is, the same clinical presentation. Our hypothesis is that many neural circuits are extremely important in schizophrenia and that these circuits are vulnerable to a number of influences. So, when any of the genes involved in these circuits are mutated, the end result is the same."

According to the researchers, the challenge remains to identify the affected biological processes and neural circuits, and to determine how they are affected.

"Although the genetics of schizophrenia are extremely complex, a coherent picture of the disease is beginning to emerge," said co-director of the study Dr. Joseph Gogos, MD, PhD, and associate professor of physiology and neuroscience at Columbia University Medical Center. "Our studies show that dozens, and perhaps hundreds, of different spontaneous mutations can raise one's risk for schizophrenia. On the surface, this is daunting, but using these new findings to understand how these mutations affect the same neural circuits, including during early fetal development, raises hopes that it may be possible to develop effective prevention and treatment strategies for the disease."

The paper is titled, "De novo gene mutations highlight patterns of genetic and neural complexity in schizophrenia." The other contributors are Bin Xu (CUMC), Iuliana Ionita-Laza (CUMC), J. Louw Roos (University of Pretoria, Pretoria, South Africa), Braden Boone (Hudson Alpha Institute for Biotechnology, Huntsville, Ala.), Scarlet Woodrick (CUMC), Yan Sun (CUMC) and Shawn Levy (Hudson Alpha Institute for Biotechnology).

The research was partially supported by National Institute of Mental Health grants MH061399 and MH077235 and the Lieber Center for Schizophrenia Research at Columbia University.

About Schizophrenia

Contrary to popular belief, schizophrenia is not a split personality; it is a chronic, severe, and disabling brain disorder that affects just over one percent of the adult population and is characterized by loss of contact with reality (psychosis), hallucinations (usually, hearing voices), firmly held false beliefs (delusions), abnormal thinking, a restricted range of emotions (flattened affect) or inappropriate and disorganized behavior, social withdrawal, and diminished motivation.

The disease often strikes in the early adult years, and although many individuals experience some recovery, many others experience substantial and lifelong disability. People with schizophrenia often have problems functioning in society and in relationships and are over-represented on disability rolls and among the homeless and imprisoned.

The precise causes of schizophrenia are not known, but current research suggests a combination of hereditary and environmental factors. Fundamentally, however, it is a biologic problem (involving changes in the brain), not one caused by poor parenting or a mentally unhealthy environment.

Since the causes of schizophrenia are not clear, treatments focus on eliminating disease symptoms. Treatments include antipsychotic medications and various psychosocial treatments.

A paper by Shizhong Han and colleagues in the current issue of Biological Psychiatry implicates a new gene in the risk for cannabis dependence. This gene, NRG1, codes for the ErbB4 receptor, a protein implicated in synaptic development and function.

The researchers set out to investigate susceptibility genes for cannabis dependence, as research has already shown that it has a strong genetic component.

To do this, they employed a multi-stage design using genetic data from African American and European American families. In the first stage, a linkage analysis, the strongest signal was identified in African Americans on chromosome 8p21. Then using a genome-wide association study dataset, they identified one genetic variant at NRG1 that showed consistent evidence for association in both African Americans and European Americans. Finally, they replicated the association of that same variant in an independent sample of African-Americans.

All together, the findings suggest that NRG1 may be a susceptibility gene for cannabis dependence.

An interesting feature of this paper is that these findings may also suggest a link between the genetics of schizophrenia and the genetics of cannabis dependence. NRG1 emerged into public awareness after a series of genetic studies implicated it in the heritable risk for schizophrenia. Subsequent studies in post-mortem brain tissue also suggested that the regulation of NRG1 was altered in the brains of individuals diagnosed with schizophrenia.

Thus, the current findings may help to explain the already established link between cannabis use and the risk for developing schizophrenia. A number of epidemiologic studies have attributed the association of cannabis use and schizophrenia to the effects of cannabis on the brain rather than a common genetic link between these two conditions.

"The current data provide a potentially important insight into the heritable risk for schizophrenia and raise the possibility that there are some common genetic contributions to these two disorders," commented Dr. John Krystal, Editor of Biological Psychiatry.

However, further research will be necessary to further confirm the role that NRG1 plays in cannabis dependence and the potential link between cannabis use and psychosis.

A new study reinforces the finding that a region of the genome involved in immune system function, called the major histocompatibility complex (MHC), is involved in the genetic susceptibility to schizophrenia.

Schizophrenia is among the most disabling psychiatric disorders. Approximately 80% of the risk for developing schizophrenia is heritable, but there has been slow progress in identifying genetic variation that contributes to the risk for schizophrenia.

The current paper contributes to this growing literature by identifying variants of genes that influence the function of the immune system which may contribute to the heritable risk for schizophrenia.

Two large, international, collaborating groups of scientists — the Wellcome Trust Case Control Consortium 2 and the Irish Schizophrenia Genomics Consortium — conducted this new study.

They first performed what is called a discovery scan, where they analyzed over 6 million genetic variants in schizophrenia patients and controls from Ireland. This allowed them to compile a list of variants that showed the strongest association signals with schizophrenia.

They then performed similar work in an independent sample of 13,195 cases and 31,021 controls from around the world in order to search for the same top 'hits'. This wealth of data was provided by the international schizophrenia genetics community. This replication work is an important scientific strategy, particularly in the field of genetics, to strengthen and support the original findings.

Using these multiple datasets and approaches, their findings lend further support for the involvement of the MHC genes in schizophrenia susceptibility.. "In this large collaborative effort, we have replicated evidence for specific risk and protective alleles at the MHC locus — a critical step teasing apart the genetic risk mechanisms involved," commented Dr. Aiden Corvin, one of the lead authors and a professor at Trinity College Dublin. "However, pinpointing specific risk genes or alleles has been challenging because this is a region of great genomic variation within and between populations."

These genetic findings also highlight an important gap in our understanding of the biology of schizophrenia. There is a long history of interest in immunologic contribution to schizophrenia including wide ranging observations linking viral infection, gluten sensitivity, changes in cytokine levels in blood and cerebrospinal fluid, and other factors to schizophrenia.

"Despite this, we have relatively little understanding how alterations in immune function are involved in the etiology and pathophysiology of this disorder," commented Dr. John Krystal, Editor of Biological Psychiatry. "Immunologic studies in schizophrenia that illuminate the nature of the contribution of variation in immune system genes to schizophrenia will be an important new direction in schizophrenia research."

A national study conducted by researchers at The Children's Hospital of Philadelphia (CHOP) shows increased use of powerful antipsychotic drugs to treat publicly insured children over the last decade. The study, published September 10 in the journal Health Services Research, found a 62 percent increase in the number of Medicaid-enrolled children ages 3 to 18 taking antipsychotics, reaching a total of 354,000 children by 2007.

Increased antipsychotic use was observed across a wide range of mental health diagnoses, and was particularly high for children with ADHD or conduct disorder, although the FDA has not approved the drugs to treat these conditions in children. In total, 65% of children prescribed antipsychotics in 2007 were using the drugs "off-label," or without FDA safety and efficacy data to support their use to treat young patients. The CHOP study is the second released this month that focuses on the use of antipsychotic drug use in children and is largest of its kind, representing 35% of children in the country.

"Given the significant proportion of off-label use of antipsychotics in children, it is reassuring that these drugs have been recognized as a priority for pediatric research by the National Institutes of Health," said David M. Rubin, MD, MSCE, a senior author of the study, attending pediatrician, and co-director of CHOP's PolicyLab. "If a child is prescribed an antipsychotic, it's important for doctors to inform parents and caregivers if the drug is being prescribed off-label, of potential side effects, and of counseling therapies that might be offered as an alternative to medication."

The frequent off-label use of antipsychotics has raised concern among many health care providers, especially in light of evidence linking antipsychotics with an increased risk of serious metabolic side effects in children, including weight gain and diabetes.

The researchers note that the increase in antipsychotic use is due to in part to an overall increase in the number of mental health diagnoses assigned to children. Researchers found a 28 percent increase in the number of children with a mental health diagnosis, but this alone did not account for the spike in prescriptions.

"We knew that the number of children prescribed antipsychotics had grown steadily over the past two decades, particularly among children with public insurance," said Meredith Matone, MHS, the study's lead author and a researcher at PolicyLab. "With this study, we wanted to learn more about why these drugs are being used so often, what diagnoses they're being used to treat, and how prescribing patterns changed over the course of the last decade."

While schizophrenia, bipolar disorder and autism were the most likely diagnoses to result in an antipsychotic prescription, children with these disorders did not make up the majority of antipsychotic users. Children with ADHD and those who were diagnosed with 3 or more concurrent mental health disorders made up the largest group of children taking antipsychotics. In 2007, 50 percent of children taking antipsychotics had a diagnosis of ADHD, and 14 percent had ADHD as their only diagnosis.

"The fact that we see an uptick in prescribing antipsychotics for many diagnoses tells us that antipsychotics are likely being used to treat specific behaviors, like aggression, that are shared among a variety of mental health diagnoses," explained Matone. "Insights like this are only available by conducting very large-scale studies like this one. Reaching an average of 15 million children a year provided the needed national perspective on medication use. Continuing to conduct population-based, public health studies is crucial to inform policies and guidelines for the use of antipsychotics for children."