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1.
Biol Psychiatry ; 94(2): 153-163, 2023 07 15.
Article in English | MEDLINE | ID: mdl-36581494

ABSTRACT

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.


Subject(s)
Induced Pluripotent Stem Cells , Schizophrenia , Humans , Schizophrenia/genetics , Schizophrenia/pathology , Calcium , Neurons/pathology
2.
Front Mol Neurosci ; 15: 994513, 2022.
Article in English | MEDLINE | ID: mdl-36533124

ABSTRACT

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.

3.
Vaccines (Basel) ; 10(9)2022 Sep 19.
Article in English | MEDLINE | ID: mdl-36146644

ABSTRACT

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.

4.
Gene ; 768: 145306, 2021 Feb 05.
Article in English | MEDLINE | ID: mdl-33189799

ABSTRACT

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.


Subject(s)
Guanine Nucleotide Exchange Factors/metabolism , Neuronal Plasticity/physiology , Protein Serine-Threonine Kinases/metabolism , Synapses/metabolism , Animals , Genome-Wide Association Study , Humans
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