Science News » NIH-funded Study Sheds Light on Abnormal Neural Function in Rare Genetic Disorder

A genetic study has identified neuronal abnormalities in the electrical activity of cortical cells derived from people with a rare genetic disorder called 22q11.2 deletion syndrome. The overexpression of a specific gene and exposure to several antipsychotic drugs helped restore normal cellular functioning. The study, funded by the National Institutes of Health (NIH) and published in Nature Medicine, sheds light on factors that may contribute to the development of mental illnesses in 22q11.2 deletion syndrome and may help identify possible targets for treatment development.

22q11.2 deletion syndrome is a genetic disorder caused by the deletion of a piece of genetic material at location q11.2 on chromosome 22. People with 22q11.2 deletion syndrome can experience heart abnormalities, poor immune functioning, abnormal palate development, skeletal differences, and developmental delays. In addition, this deletion confers a 20-30% risk for autism spectrum disorder (ASD) and an up to 30-fold increase in risk for psychosis. 22q11.2 deletion syndrome is the most common genetic copy number variant found in those with ASD, and up to a quarter of people with this genetic syndrome develop a schizophrenia spectrum disorder.

“This is the largest study of its type in terms of the number of patients who donated cells, and it is significant for its focus on a key genetic risk factor for mental illnesses,” said David Panchision, Ph.D., chief of the Developmental Neurobiology Program at the NIH’s National Institute of Mental Health. “Importantly, this study shows consistent, specific patient-control differences in neuronal function and a potential mechanistic target for developing new therapies for treating this disorder.”

While some effects of this genetic syndrome, such as cardiovascular and immune concerns, can be successfully managed, the associated psychiatric effects have been more challenging to address. This is partly because the underlying cellular deficits in the central nervous system that contribute to mental illnesses in this syndrome are not well understood. While recent studies of 22q11.2 deletion syndrome in rodent models have provided some important insights into possible brain circuit-level abnormalities associated with the syndrome, more needs to be understood about the neuronal pathways in humans.

To investigate the neural pathways associated with mental illnesses in those with 22q11.2 deletion syndrome, Sergiu Pasca, M.D., associate professor of psychiatry and behavioral sciences at Stanford University, Stanford, California, along with a team of researchers from several other universities and institutes, created induced pluripotent stems cells — cells derived from adult skin cells reprogramed into an immature stem-cell-like state — from 15 people with 22q11.2 deletion and 15 people without the syndrome. The researchers used these cells to create, in a dish, three-dimensional brain organoids that recapitulate key features of the developing human cerebral cortex.

“What is exciting is that these 3D cellular models of the brain self-organize and, if guided to resemble the cerebral cortex, for instance, contain functional glutamatergic neurons of deep and superficial layers and non-reactive astrocytes and can be maintained for years in culture. So, there is a lot of excitement about the potential of these patient-derived models to study neuropsychiatric disease,” said Dr. Pasca.

The researchers analyzed gene expression in the organoids across 100 days of development. They found changes in the expression of genes linked to neuronal excitability in the organoids that were created using cells from individuals with 22q11.2 deletion syndrome. These changes prompted the researchers to take a closer look at the properties associated with electrical signaling and communication in these neurons. One way neurons communicate is electrically, through controlled changes in the positive or negative charge of the cell membrane. This electrical charge is created when ions, such as calcium, move into or out of the cell through small channels in the cell’s membrane. The researchers imaged thousands of cells and recorded the electrical activity of hundreds of neurons derived from individuals with 22q11.2 deletion syndrome and found abnormalities in the way calcium was moved into and out of the cells that were related to a defect in the resting electrical potential of the cell membrane.

A gene called DGCR8 is part of the genetic material deleted in 22q11.2 deletion syndrome, and it has been previously associated with neuronal abnormalities in rodent models of this syndrome. The researchers found that heterozygous loss of this gene was sufficient to induce the changes in excitability they had observed in 22q11.2-derived neurons and that overexpression of DGCR8 led to partial restoration of normal cellular functioning. In addition, treating 22q11.2 deletion syndrome neurons with one of three antipsychotic drugs (raclopride, sulpiride, or olanzapine) restored the observed deficits in resting membrane potential of the neurons within minutes.

“We were surprised to see that loss in control neurons and restoration in patient neurons of the DGCR8 gene can induce and, respectively, restore the excitability, membrane potential, and calcium defects,” said Pasca. “Moving forward, this gene or the downstream microRNA(s) or the ion channel/transporter they regulate may represent novel therapeutic avenues in 22q11.2 deletion syndrome.”

Reference

Khan, T. A., Revah, O., Gordon, A., Yoon, S., Krawisz, A. K., Goold, C., Sun, Y., Kim, C., Tian, Y., Li, M., Schaepe, J. M., Ikeda, K., Amin, N. D., Sakai, N., Yazawa, M., Kushan, L., Nishino, S., Porteus, M. H., Rapoport, J. L. … Paşca, S. (2020). Neuronal defects in a human cellular model of 22q11.2 deletion syndrome. Nature Medicine. doi: 10.1038/s41591-020-1043-9

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About the National Institute of Mental Health (NIMH): The mission of the NIMH is to transform the understanding and treatment of mental illnesses through basic and clinical research, paving the way for prevention, recovery and cure. For more information, visit the NIMH website.

About the National Institutes of Health (NIH): NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit the NIH website.

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Original Article

Scientific Meeting » NIMH Livestream Event: Suicide Prevention Strategies

NIMH Livestream Event: Suicide Prevention Strategies

Date/Time:

Suicide is a major public health concern. More than 48,000 people die by suicide each year in the United States, and it was the 10th leading cause of death overall in 2018. Suicide is complicated and tragic, but it is often preventable.

September is National Suicide Prevention Awareness Month, a time to help raise awareness and share information about this important public health concern. Although the COVID-19 pandemic’s impact on suicide is still unknown, the slow but steady increases in the U.S. suicide rate remain a concern.

The National Institute of Mental Health (NIMH) will host a livestream event on Wednesday, September 23, 2020, from 2:00 – 2:30 p.m. ET, to discuss the latest in suicide prevention research, including ways to identify risk, and effective prevention strategies. Joshua Gordon, M.D., Ph.D., Director of NIMH, will moderate this discussion with Jane Pearson, Ph.D., Special Advisor to the NIMH Director on Suicide Research, and Stephen O’Connor, Ph.D., chief of the Suicide Prevention Research Program in the NIMH Division of Services and Intervention Research.

Participating is easy.

  • Watch the livestream event on NIMH’s Facebook or Twitter feeds. You must have either a Facebook or Twitter account to watch.
  • Follow NIMH on Facebook or Twitter for updates on the livestream event and other information about mental health research.
  • Refresh NIMH’s Facebook or Twitter feeds at 2 p.m. ET on September 23rd to watch the livestream discussion.

The livestream will be archived on NIMH’s website and Facebook page so you can access it after the event is over.

Note: The experts cannot provide specific medical advice or referrals. Please consult with a qualified health care provider for diagnosis, treatment, and answers to your personal questions. If you need help finding a provider, visit www.nimh.nih.gov/findhelp. If you or someone you know is in crisis, please call the National Suicide Prevention Lifeline at 1-800-273-TALK (8255); En Español 1-888-628-9454.

Original Article

Blog Post » Addressing the Crisis of Black Youth Suicide

Each September, people in the U.S. and around the world observe Suicide Prevention Awareness Month, a time to help raise awareness and share information about this important public health concern. As director of the National Institute of Mental Health (NIMH), I have made suicide prevention one of my top priorities, and although I have written about suicide in the past, I wanted to revisit this topic to bring attention to this critical area of concern.

One often overlooked aspect of the rising rates of suicide in the U.S. is its impact on youth — and in particular, its impact on Black youth. Black people face increased rates of risk factors, including experiences of racism, higher rates of unemployment and financial and food insecurity, disparities in other aspects of health, and limited access to care, all of which result in an increased burden of mental illness in black communities. Despite this heavy burden, Black people and individuals in other racial and ethnic minority groups have historically had relatively low rates of suicide. But this has been changing recently, especially for Black youth. As of 2018, suicide became the second leading cause of death in Black children aged 10-14, and the third leading cause of death in Black adolescents aged 15-19. By combining data from 2001 to 2015, researchers were able to examine suicides among children ages 12 and younger and found that Black children were more likely to die by suicide than their White peers.

This crisis of Black youth suicide is beginning to receive the attention it deserves. Congresswoman Bonnie Watson Coleman (D-N.J.) and the Congressional Black Caucus deserve credit for raising awareness of the issue and for establishing the Emergency Taskforce on Black Youth Suicide and Mental Health. Their report, Ring the Alarm: The Crisis of Black Youth Suicide in America, was released in December 2019. This report describes key research findings related to suicide among Black youth. Most importantly, it provides research, policy, and practice recommendations to address this issue, such as improving research funding of minority scientists and increasing funding of research focused on Black youth suicide and Black youth mental health.

More research is needed on how suicide risk develops among Black youth, and how it can be best prevented. Significant questions remain in terms of understanding and predicting suicide risk among Black youth — while some risk factors have been well-researched and are clear (e.g., gender, victim of bullying and bullying others, LGBTQ+ discrimination, exposure to trauma, racial discrimination), there are other risk factors that are less clear. For example, some research suggests that Black adolescents who have contemplated or attempted suicide are less likely to have been diagnosed with a mental illness. Another significant risk factor is access to firearms — research points to higher rates of Black youth mortality due to firearms compared to other racial/ethnic groups — which is why we’re supporting infrastructure to improve research on firearm safety for youth.

One factor that may be contributing to increases in the risk of suicide in Black youth may be disparities in access to mental health services. Black youth continue to be less likely to receive mental health treatment for depression when needed, compared to White youth. Rates of engagement in and completion of treatments for depression are lower for Black adolescents (compared to White adolescents), often due to negative perceptions of services and providers and reluctance to acknowledge symptoms. Black youth are also significantly less likely than White youth to receive outpatient treatment even after a suicide attempt.

The good news is that NIMH-funded research has begun to point the way towards better risk identification and effective interventions that can help reverse these trends. Implementing universal screening for suicide risk using the Ask Suicide-Screening Questions toolkit, developed by investigators in the NIMH Intramural Research Program, can identify youth at risk, including Black youth. And, targeted efforts such as school-based mental health clinics can improve engagement in mental health care among Black youth with depression.

Nonetheless, we need considerably more research focused on solutions for Black children and adolescents if we are to truly make a difference for those in need. Accordingly, NIMH continues to expand opportunities for scientists interested in studying these issues, as articulated in our recent Notice of Special Interest (NOSI) in Research on Risk and Prevention of Black Youth Suicide. Other initiatives, including a call to establish Practice-Based Suicide Prevention Research Centers, though broader, are also designed to support work in minority communities and address disparities that affect Black youth. And we continue to look for additional opportunities to support science aimed at addressing this crisis. Black youths’ lives matter, and NIMH research must be aimed at saving lives and alleviating suffering in Black communities in need.

References

Breland-Noble, A. M., & AAKOMA Project Adult Advisory Board (2012). Community and treatment engagement for depressed African American youth: the AAKOMA FLOA pilot. Journal of Clinical Psychology in Medical Settings, 19(1), 41–48. https://doi.org/10.1007/s10880-011-9281-0

Bridge, J. A., Horowitz, L. M., Fontanella, C. A., Sheftall, A. H., Greenhouse, J., Kelleher, K. J., & Campo, J. V. (2018). Age-related racial disparity in suicide rates among US youths from 2001 through 2015. JAMA Pediatrics, 172(7), 697–699. https://doi.org/10.1001/jamapediatrics.2018.0399

Cummings, J. R., Ji, X., Lally, C., & Druss, B. G. (2019). Racial and ethnic differences in minimally adequate depression care among Medicaid-enrolled youth. Journal of the American Academy of Child and Adolescent Psychiatry, 58(1), 128–138. https://doi.org/10.1016/j.jaac.2018.04.025

DeVylder, J. E., Ryan, T. C., Cwik, M., Wilson, M. E., Jay, S., Nestadt, P. S., Goldstein, M., & Wilcox, H. C. (2019). Assessment of selective and universal screening for suicide risk in a pediatric emergency department. JAMA Network Open, 2(10), e1914070. https://doi.org/10.1001/jamanetworkopen.2019.14070

Fowler, K. A., Dahlberg, L. L., Haileyesus, T., Gutierrez, C., & Bacon, S. (2017). Childhood firearm injuries in the United States. Pediatrics, 140(1), e20163486. https://doi.org/10.1542/peds.2016-3486

Joe, S., Baser, R. S., Neighbors, H. W., Caldwell, C. H., & Jackson, J. S. (2009). 12-month and lifetime prevalence of suicide attempts among black adolescents in the national survey of American life. Journal of the American Academy of Child and Adolescent Psychiatry, 48(3), 271–282. https://doi.org/10.1097/CHI.0b013e318195bccf

Lindsey, M. A., Chambers, K., Pohle, C., Beall, P., & Lucksted, A. (2013). Understanding the behavioral determinants of mental health service use by urban, under-resourced black youth: Adolescent and caregiver perspectives. Journal of Child and Family Studies, 22(1), 107–121. https://doi.org/10.1007/s10826-012-9668-z

Musci, R. J., Hart, S. R., Ballard, E. D., Newcomer, A., Van Eck, K., Ialongo, N., & Wilcox, H. (2016). Trajectories of suicidal ideation from sixth through tenth grades in predicting suicide attempts in young adulthood in an urban African American cohort. Suicide and Life-Threatening Behavior, 46(3), 255–265. https://doi.org/10.1111/sltb.12191

Original Article

Scientific Meeting » Virtual Workshop: Genes to Biology: Integrative Systematic Approaches for Revealing Biological Functions of Psychiatric Risk Genes and Alleles

Virtual Workshop: Genes to Biology: Integrative Systematic Approaches for Revealing Biological Functions of Psychiatric Risk Genes and Alleles

Date/Time:

About the Workshop:

The purpose of this workshop is to stimulate discussions among experts to identify systematic experimental approaches to gain comprehensive insights into psychiatric disease mechanisms based on human genetic findings. This Genes to Biology (G2B) framework is envisioned as a tiered approach from broad, unbiased high-throughput screens to deep, targeted low-throughput investigations. Given that the effects of coding mutations are more readily interpretable, this workshop focuses on identifying current or emerging scalable technologies for surveying the biological impact of all risk alleles in genes with an increased burden of damaging mutations in neurodevelopmental and psychiatric disorders. The hope is to develop a systematic framework for gaining a meaningful biological understanding of the genetic risk underlying psychiatric disorders and make much-needed headway into identifying disease mechanisms.

Meeting Goals:

  • Identify opportunities and challenges for developing a transformative framework to advance the work on systematic functional dissections of psychiatric risk genes.
  • Focus: conceptual approaches, high-throughput technologies, scalable assays, mechanistic and computational inferences.

Moderators:

11:00 am – 12:00 pm: Conceptual discussion
12:00 – 1:20 pm: Scalable technologies
1:30 – 2:50 pm: Functional assays/understanding mechanisms
3:00 – 4:30 pm: Future directions/Next steps
4:30 pm: Adjourn

Registration: Please register online for this free event to confirm your attendance. Registration will close on Friday, September 18th.

Original Article

Scientific Meeting » Report Out Session of the HIV-Related Intersectional Stigma Research Advances and Opportunities Workshop

Report Out Session of the HIV-Related Intersectional Stigma Research Advances and Opportunities Workshop

Date/Time:

Sponsored by:

National Institutes of Health (NIH) Office of AIDS Research and National Institute of Mental Health (NIMH) Division of AIDS Research

On September 18, 2020, join the NIH Office of AIDS Research and the NIMH Division of AIDS Research for a discussion about the outcomes of recent meetings of four workgroups focused on HIV-related intersectional stigma research advances and opportunities. The goal of this virtual workshop is to advance HIV prevention and treatment science, inform the Ending the HIV Epidemic (EHE) initiative, and bolster HIV efforts worldwide. During the workshop, researchers, government officials, and community partners will report on the following:

  • Development of a common understanding of the concept of intersectional stigma and discrimination within the context of HIV prevention and care;
  • Harmonization of methods and measurements of intersectional stigma and discrimination;
  • Identification of opportunities within, across, and beyond EHE jurisdictions to monitor intersectional stigma and discrimination;
  • Review of evidence-based interventions designed to reduce intersectional stigma and discrimination;
  • Integration and tailoring of intersectional interventions to advance EHE goals and improve HIV prevention and treatment outcomes globally; and
  • Next steps to address research opportunities and advance implementation plans.

Registration:

Please register online to attend this free event.

Original Article