Excitatory Dysfunction Drives Network and Calcium Handling Deficits in 16p11.2 Duplication Schizophrenia Induced Pluripotent Stem Cell-Derived Neurons.

BACKGROUND: Schizophrenia (SCZ) is a debilitating psychiatric disorder with a large genetic contribution; however, its neurodevelopmental substrates remain largely unknown. Modeling pathogenic processes in SCZ using human induced pluripotent stem cell-derived neurons (iNs) has emerged as a promising strategy. Copy number variants confer high genetic risk for SCZ, with duplication of the 16p11.2 locus increasing the risk 14.5-fold. METHODS: To dissect the contribution of induced excitatory neurons (iENs) versus GABAergic (gamma-aminobutyric acidergic) neurons (iGNs) to SCZ pathophysiology, we induced iNs from CRISPR (clustered regularly interspaced short palindromic repeats)-Cas9 isogenic and SCZ patient-derived induced pluripotent stem cells and analyzed SCZ-related phenotypes in iEN monocultures and iEN/iGN cocultures. RESULTS: In iEN/iGN cocultures, neuronal firing and synchrony were reduced at later, but not earlier, stages of in vitro development. These were fully recapitulated in iEN monocultures, indicating a primary role for iENs. Moreover, isogenic iENs showed reduced dendrite length and deficits in calcium handling. iENs from 16p11.2 duplication-carrying patients with SCZ displayed overlapping deficits in network synchrony, dendrite outgrowth, and calcium handling. Transcriptomic analysis of both iEN cohorts revealed molecular markers of disease related to the glutamatergic synapse, neuroarchitecture, and calcium regulation. CONCLUSIONS: Our results indicate the presence of 16p11.2 duplication-dependent alterations in SCZ patient-derived iENs. Transcriptomics and cellular phenotyping reveal overlap between isogenic and patient-derived iENs, suggesting a central role of glutamatergic, morphological, and calcium dysregulation in 16p11.2 duplication-mediated pathogenesis. Moreover, excitatory dysfunction during early neurodevelopment is implicated as the basis of SCZ pathogenesis in 16p11.2 duplication carriers. Our results support network synchrony and calcium handling as outcomes directly linked to this genetic risk variant.

A developmental delay linked missense mutation in Kalirin-7 disrupts protein function and neuronal morphology.

The Rac1 guanine exchange factor Kalirin-7 is a key regulator of dendritic spine morphology, LTP and dendritic arborization. Kalirin-7 dysfunction and genetic variation has been extensively linked to various neurodevelopmental and neurodegenerative disorders. Here we characterize a Kalirin-7 missense mutation, glu1577lys (E1577K), identified in a patient with severe developmental delay. The E1577K point mutation is located within the catalytic domain of Kalirin-7, and results in a robust reduction in Kalirin-7 Rac1 Guanosine exchange factor activity. In contrast to wild type Kalirin-7, the E1577K mutant failed to drive dendritic arborization, spine density, NMDAr targeting to, and activity within, spines. Together these results indicate that reduced Rac1-GEF activity as result of E1577K mutation impairs neuroarchitecture, connectivity and NMDAr activity, and is a likely contributor to impaired neurodevelopment in a patient with developmental delay.

COVID-19 Vaccine Hesitancy among Health Professional Students: Cross-Sectional Data from the First Wave of the HOLISTIC Cohort Study.

Vaccine hesitancy has been observed around the world, but there is a paucity of data among a broad range of U.S. health professional students. The goal of this report is to present findings about COVID-19 vaccine hesitancy among a cross-section of U.S. health professional students and determine if hesitancy varies by demographic characteristics, health science college, and other factors. A cross-sectional analysis of HOLISTIC Cohort Study participants enrolled from April 14 2021 to May 5 2021 at seven health sciences colleges in the University of Illinois Chicago was used. Exploratory and confirmatory factor analysis were used to evaluate vaccine hesitancy items and identify domains. Among 555 health professional students, three domains (perceived benefit, trustworthiness, and risk) contribute to vaccine hesitancy. Significant differences were observed in the domains among students of different races as well as vaccination history. Compared to students in the College of Medicine, students in the Colleges of Applied Health Science (OR 0.43; CI [0.19-0.96]), Pharmacy (OR 0.38; CI [0.17-0.87]), Nursing (OR 0.35; CI [0.16-0.78]), and Social Work (OR 0.30; CI [0.11-0.78]) reported lower perceived benefit. Compared to students in the College of Medicine, students in the College of Applied Health Sciences (OR 0.39; CI [0.17-0.94]), Dentistry (OR 0.27; CI [0.10-0.76]), Nursing (OR 0.38; CI [0.16-0.94]), and Social work (OR 0.31; CI [0.11-0.86]) reported more trustworthiness and more concerns about risk (OR 2.80; CI [1.15-6.81] for College of Applied Health Sciences, OR 9.12; CI [2.80-29.75] for Dentistry, OR 3.77; CI [1.47-9.65] for Nursing, OR 3.14; CI [1.02-9.67] for Social Work). Our findings suggest the need for a tailored vaccination strategy among different subgroups of health professional students.

Health professional students at the University of Illinois Chicago (HOLISTIC) Cohort Study: A protocol.

OBJECTIVES: The objectives of the HOLISTIC Cohort Study are to establish a prospective cohort study covering a period of three years that characterizes the health of students within and across health professional education programs at the University of Illinois Chicago (UIC) during the coronavirus disease 2019 (COVID-19) pandemic, implement an interprofessional student research team, and generate a meaningful dataset that is used to inform initiatives that improve student health. This report describes the protocol of the HOLISTIC Cohort Study, including survey development, recruitment strategy, and data management and analysis. METHODS: An interprofessional student research team has been organized with the goal of providing continuous assessment of study design and implementation across the seven health science colleges (applied health sciences, dentistry, medicine, nursing, pharmacy, public health, and social work) at the University of Illinois Chicago in Chicago, IL. To be eligible to participate in the HOLISTIC Cohort Study, students are required to be 1) age 18 years or older; 2) enrolled full- or part-time in one or more of UIC's seven health science colleges; and 3) enrolled in a program that prepares its graduates to enter a healthcare profession. The study protocol includes a series of three recruitment waves (Spring 2021 [April 14, 2021, to May 5, 2021; completed], Spring 2022, Spring 2023). In the first recruitment wave, eligible students were sent an invitation via electronic mail (e-mail) to complete an online survey. The online survey was based on the U.S. Centers for Disease Control and Prevention's Behavioral Risk Factor Surveillance System 2019 survey and the 2014 World Health Organization Report of the Strategic Advisory Group of Experts Working Group Vaccine Hesitancy Scale. Electronic informed consent and study data are collected and managed using Research Electronic Data Capture (REDCap) tools. This study utilizes convenience sampling from all seven health science colleges at UIC with a target recruitment total of 2,000 participants. DISCUSSION AND FUTURE DIRECTIONS: A total of 555 students across all seven health science colleges (10.8% of 5,118 students who were invited; 27.6% of target sample size) enrolled in the cohort during the first recruitment wave. The pilot data establishes the feasibility of the study during the COVID-19 pandemic. Adaptations to overcome barriers to study implementation, including the use of remote, rather than in-person, study meetings, staff training, and participant recruitment are discussed. For the second and third waves of recruitment, the student research team will seek institutional review board (IRB) approval to implement additional enrollment strategies that are tailored to each health science college, such as online newsletters, virtual townhalls, flyers on bulletin boards near classrooms tailored to each health science college.

KALRN: A central regulator of synaptic function and synaptopathies.

The synaptic regulator, kalirin, plays a key role in synaptic plasticity and formation of dendritic arbors and spines. Dysregulation of the KALRN gene has been linked to various neurological disorders, including autism spectrum disorder, Alzheimer's disease, schizophrenia, addiction and intellectual disabilities. Both genetic and molecular studies highlight the importance of normal KALRN expression for healthy neurodevelopment and function. This review aims to give an in-depth analysis of the structure and molecular mechanisms of kalirin function, particularly within the brain. These data are correlated to genetic evidence of patient mutations within KALRN and animal models of Kalrn that together give insight into the manner in which this gene may be involved in neurodevelopment and the etiology of disease. The emerging links to human disease from post-mortem, genome wide association (GWAS) and exome sequencing studies are examined to highlight the disease relevance of kalirin, particularly in neurodevelopmental diseases. Finally, we will discuss efforts to pharmacologically regulate kalirin protein activity and the implications of such endeavors for the treatment of human disease. As multiple disease states arise from deregulated synapse formation and altered KALRN expression and function, therapeutics may be developed to provide control over KALRN activity and thus synapse dysregulation. As such, a detailed understanding of how kalirin regulates neuronal development, and the manner in which kalirin dysfunction promotes neurological disease, may support KALRN as a valuable therapeutic avenue for future pharmacological intervention.