Tag: Schizophrenia

Neurodevelopment-Related Gene Deficiency

Advertisements

Findings may lead to clues for possible treatments for autism spectrum disorders and schizophrenia

Credit: CWRU

Lin Mei, the Allen C. Holmes Professor of Neurological Diseases and chair of the Department of Neurosciences at the Case Western Reserve University School of Medicine

CLEVELAND—Researchers at the Case Western Reserve University School of Medicine have identified that a gene critical to clearing up unnecessary proteins plays a role in brain development and contributes to the development of autism spectrum disorders (ASD) and schizophrenia.

The discovery, published today in Neuron (embargo lifts online Nov. 25 at 11 a.m.), provides important insight into the mechanism of both diseases—a possible step toward finding how to treat the disorders.

Cullin 3 is a core component of an E3 ubiquitin ligase responsible for the cell’s clearance of proteins. Mutations of its gene CUL3 have been associated with autism and schizophrenia. However, pathologic mechanisms of CUL3 deficiency have been unclear.

Advertisements

“CUL3 is abundant in the brain, yet little is known of its function,” said Lin Mei, the Allen C. Holmes Professor of Neurological Diseases and chair of the Department of Neurosciences at the Case Western Reserve University School of Medicine. “Here, we show that CUL3 is critical for brain development and communication between cells in the brain.”

Mei, also director of the Cleveland Brain Health Initiative, is the principal investigator with research assistants Zhaoqi Dong and Wenbing Chen. (The published research is titled “CUL3 deficiency causes social deficits and anxiety-like behaviors by impairing excitation-inhibition balance through the promotion of Cap-dependent translation.”)

ASD is a complicated condition that includes difficulty with communication and social interaction, obsessive interests and repetitive behaviors. It affects 1 in 59 children in the United States, according to a recent report by the Centers for Disease Control. Schizophrenia affects about 1 in 100 people worldwide. However, autism and schizophrenia remain among the most mysterious disorders.

Mei and his team studied how CUL3 mutation impacts the brain in mouse models. The researchers were able to demonstrate that altering the gene in mouse models can cause similar social problems that appear in people with these disorders.

Normal mice would spend more time with a mouse over an inanimate object, Mei said. But CUL3-mutant mice couldn’t differentiate between a mouse and an inanimate object, showing a problem with social preference.

Advertisements

In another test, normal mice would spend more time with an unfamiliar mouse over a familiar one. But CUL3-mutant mice couldn’t remember seeing a familiar mouse, suggesting a problem of social memory. Also, CUL3-mutant mice were more anxious than normal mice.

Researchers at Beijing Normal University and the Louis Stokes Cleveland Veterans Affairs Medical Center contributed to the research.

Case Western Reserve University is one of the country’s leading private research institutions. Located in Cleveland, we offer a unique combination of forward-thinking educational opportunities in an inspiring cultural setting. Our leading-edge faculty engage in teaching and research in a collaborative, hands-on environment. Our nationally recognized programs include arts and sciences, dental medicine, engineering, law, management, medicine, nursing and social work. About 5,100 undergraduate and 6,700 graduate students comprise our student body. Visit case.edu to see how Case Western Reserve thinks beyond the possible.

Medicinal Cannabis Research

Advertisements

Researchers will look at how CBD might help remedy schizophrenia, rheumatoid arthritis, insomnia, alcohol dependence and anorexia anxiety

The Center for Medicinal Cannabis Research (CMCR) at University of California San Diego School of Medicine, the nation’s oldest research center for scientific inquiry into the safety and efficacy of cannabis, has announced $3 million in research grants to explore new applications of cannabis for a number of novel medical applications.

Advertisements

The cannabis plant produces a number of compounds called cannabinoids, the most widely known of which are tetrahydrocannabinol (THC), its principle psychoactive agent, and cannabidiol (CBD), which has been linked to reduced pain, anxiety and inflammation in previous studies. The five new studies all focus on CBD.

“Within the medical community, there is a lot of interest in the role of medical cannabis and CBD,” said Igor Grant, MD, Distinguished Professor in the Department of Psychiatry and CMCR director. “There is a hope that it could be yet another useful agent in some of these conditions, which are difficult to treat or disabling.”

The five grants are funded by California Proposition 64, which was passed on the November 8, 2016 ballot and legalized recreational marijuana in the state. The measure allocated tax revenue for research on potential new drugs, treatment and health and safety programs related to marijuana and medical cannabis.

Advertisements

This year marks CMCR’s first such funding. All five grants are for proof-of-principle studies that would seek to establish the basis for future research.

Effects of Cannabidiol versus Placebo as an Adjunct to Treatment in Early Psychosis

The $825,000 grant was awarded to Kristin Cadenhead, MD, professor of psychiatry at UC San Diego School of Medicine, and colleagues, who will explore whether medical cannabis could serve as an alternative treatment for patients facing early psychosis, a time when traditional treatments, such as antipsychotic medications, are moderately effective but produce debilitating side effects.

Therapeutic Response of Cannabidiol in Rheumatoid Arthritis

The $825,000 grant was awarded to Veena Ranganath, MD, a rheumatologist at UCLA Medical Center. Ranganath’s research focuses on CBD’s use an anti-inflammatory agent, an application she hopes to exploit in treating rheumatoid arthritis, a chronic autoimmune condition that affects an estimated 1.5 million persons in the United States.

Cannabidol for Sedative/Hypnotic-sparing Management of Insomnia in Adults

The $825,000 grant was awarded to Mariana Cherner, PhD, professor of psychiatry at UC San Diego School of Medicine, and colleagues, who will investigate whether CBD might be a viable alternative for sleeping pills among patients with chronic sleep disorders.

Advertisements

“Sleeping pills are moderately safe but they can also be habit-forming and they do have side effects, particularly in older people,” said Grant. “So many people are prescribed sleeping pills so there’s good reason to look for something that might be safer and not have that side effect profile.”

Cannabidiol as a Strategy to Treat Alcohol Dependence

The $300,000 grant was awarded to Giordano de Guglielmo, PhD, assistant adjunct professor in the UC San Diego Skaggs School of Pharmacy and Pharmaceutical Sciences, and colleagues. This study is the only one of the five using an animal model. It will look at the role CBD might play in reducing alcohol cravings and withdrawal syndromes among alcohol-addicted rats, with findings perhaps applicable to future human research.

The Role of Cannabidiol in Regulating Meal Time Anxiety in Anorexia Nervosa

The $300,000 grant was awarded to Emily Gray, MD, associate clinical professor of psychology at UC San Diego School of Medicine, and colleagues, who will explore whether CBD can help reduce a core symptom of anorexia — anxiety about food — and whether or not that reduction helps patients also reduce their food aversions overall.

A second round of CMCR grants is scheduled for 2020.

Harvard University to Launch Center for Autism Research

Advertisements

Autism and related disorders—a constellation of neurodevelopmental conditions affecting one in 59 children in the United States alone—have become one of modern medicine’s most confounding mysteries. The condition is believed to arise from the complex interplay between genes and environment, yet its basic biology remains largely a black box.

Now, a new research effort at Harvard University led by Harvard Medical School is poised to identify the biologic roots and molecular changes that give rise to autism and related disorders with the goal of informing the development of better diagnostic tools and new therapies. Harvard University has received a $20 million gift from philanthropists Lisa Yang and Hock Tan, an alumnus of Harvard Business School, to establish The Hock E. Tan and K. Lisa Yang Center for Autism Research at Harvard Medical School. The latest gift brings the total autism-related research funding provided by Yang and Tan to nearly $70 million.

Advertisements

The center will serve as a hub that brings together the diverse expertise of scientists and clinicians working throughout Harvard University, Harvard Medical School and its affiliated hospitals.

“There is an urgent need to understand the fundamental biology of autism,” said Michael Greenberg, chair of the Department of Neurobiology at Harvard Medical School and the center’s inaugural faculty leader. “I strongly believe that the multidisciplinary expertise convened by this center will propel us into a new era of autism research, enhancing our understanding of the condition and yielding critical new insights into its causes. This generous gift will be transformative for the field.”

Advertisements

Working under the premise that autism’s complexity demands the cross-pollination of diverse expertise across different modes of scientific inquiry, the center will encompass the efforts of basic, translational and clinical scientists from the entire Harvard ecosystem. The center will have its administrative home within the Harvard Brain Science Initiative, which brings together researchers from Harvard Medical School and its affiliated hospitals as well as from the Harvard Faculty of Arts and Sciences, the Harvard T.H. Chan School of Public Health and the Harvard John A. Paulson School of Engineering and Applied Sciences. “Neuroscience has reached a unique inflection point. Advances such as single-cell analysis and optogenetics, coupled with an unprecedented ability to visualize molecular shifts down to the minutest level, will enable today’s researchers to tackle a disorder as dauntingly complex as autism,” said Harvard Medical School Dean George Q. Daley.

“Medical history has taught us that truly transformative therapies flow only from a clear understanding of the fundamental biology that underlies a condition,” Daley added. “This gift will allow our researchers to generate critical insights about autism and related disorders.”

Advertisements

Investigators at the new Harvard University center will collaborate with peer researchers at MIT and complement efforts already underway at The Hock E. Tan and K. Lisa Yang Center for Autism Research at the McGovern Institute for Brain Research at MIT, with the unique strengths of each institution converging toward a shared goal: understanding the roots of autism, explaining the condition’s behavior and evolution and translating those insights into novel approaches to treat its symptoms.

“In a short time, the Tan-Yang Center at the McGovern Institute has supported groundbreaking research we believe will change our understanding of autism,” said Robert Desimone, the director of the sibling center at MIT. “We look forward to joining forces with the new center at Harvard, to greatly accelerate the pace of autism-related research.”

“We are excited and hopeful that these sibling centers at Harvard and MIT—two powerhouses of biomedical research—will continue to collaborate in a synergistic way and bring about critical new insights to our understanding of autism,” Yang said. Yang is a former investment banker who has devoted much of her time to mental health advocacy. Tan is president and CEO of Broadcom, a global infrastructure technology company. 

Advertisements

Autism-spectrum disorders—neurodevelopmental conditions that typically emerge in the first few years of life—are marked by a cluster of symptoms, impaired social interactions and compromised communication skills. Yet exactly what portion of these cases is rooted in genetic mutations and how they are influenced by environmental factors is an area of lingering uncertainty. Another key area of uncertainty is how much of autism’s fundamental features arise in the brain and what influence organs and systems outside of the brain might have.

Two of the new center’s initial areas of inquiry will address these critical gaps in knowledge.

One group of researchers will focus on understanding precisely what goes awry during critical windows in the first two years of life—a period marked by rapid brain development, great neuroplasticity and intense wiring of the brain’s circuits. This is also the typical window of autism diagnosis. The scientists will try to understand what molecular, cellular or neural-circuitry changes underlie autism-fueling processes during this stage. Identifying such critical changes can help illuminate how experiences modulate brain development in individuals with autism.

Advertisements

Another group of researchers will examine the role of factors arising from organs and organ systems outside the brain that may drive autism risk. For example, the peripheral nervous system—made up of nerve cells throughout the body that act as nodes to collect and transmit signals to the brain—has emerged as a central player in the development of autism.

Heightened sensitivity to even light touch is a common feature in autism and one of the disorder’s many perplexing symptoms. Recent research from neurobiologists and geneticists at Harvard Medical School has not only identified the molecular changes that give rise to heightened touch sensitivity in autism-spectrum disorders but also points to a possible treatment for the condition.

Why Males Are More at Risk Than Females For Neurodevelopmental Disorders?

Newswise — Researchers have recently begun to realize that biological sex plays a key role in disease risk. Sex plays a role in hypertension, diabetes, arthritis – and in many neurological and psychiatric disorders. Depression and anxiety affect females more, while neurodevelopmental disorders, including autism spectrum disorders, early onset schizophrenia, and attention deficit hyperactivity, affect more males. Males are also more sensitive to prenatal insults, such as gestational stress, maternal infection and drug exposure.

//pagead2.googlesyndication.com/pagead/js/adsbygoogle.js (adsbygoogle = window.adsbygoogle || []).push({}); ‘);//pagead2.googlesyndication.com/pagead/js/adsbygoogle.js

//cdn.chitika.net/getads.jsTo better understand the molecular underpinnings of this disparity, Tracy Bale of the University of Maryland School of Medicine, along with several colleagues, focused on a molecule that plays a key role in placental health. In a study of mice, they found that the molecule, O-linked N-acetylglucosamine transferase (OGT) works by establishing sex-specific patterns of gene expression. The study was published this week in the journal Nature Communications. OGT seems to work via an epigenetic modification that broadly controls transcription, H3K27me3. Epigenetics is the study of changes in how genes are expressed. Dr. Bale showed that high levels of H3K27me3 in the female placenta produce resilience to stress experienced by the mother. This indicates at least one molecular pathway that allows females to be more resilient to maternal stress than males. “This pathway could help explain why we see this profound neurodevelopmental difference in humans,” said Dr. Bale. “OGT and H3K27me3 in the placenta are crucial to a lot of protein encoding that occurs during pregnancy, and so this process has a lot of downstream effects. The OGT gene is on the X chromosome, and seems to provide a level of protection for the female fetus to perturbations in the maternal environment.” Dr. Bale has focused much of her research on the links between stress and subsequent risk for neurodevelopmental disorders, including autism and schizophrenia in offspring. Her previous work on the placenta has found novel sex differences that may predict increased prenatal risk for disease in males. She has previously found that, in mice, a father’s stress can affect the brain development of offspring. This stress can alter the father’s sperm, which can alter the brain development of the child. Dr. Bale has also found that male mice experiencing chronic mild stress have offspring with a reduced hormonal response to stress; this response has been linked to some neuropsychiatric disorders, including PTSD. This suggests that even mild environmental challenges can have a significant effect on the health of offspring.