Modeling ADHD using induced pluripotent stem cells-derived neural cells

Duration
ongoing

ADHD is a prevalent neurodevelopmental and mental health disorder in children and adolescents that frequently continues into adulthood. The aetiology and pathophysiology of ADHD remain unidentified; however, evidence suggests that genetic and environmental factors likely impact brain maturation and development. Existing models for ADHD, whether in vivo or in vitro, do not completely replicate the full range of traits or genetic makeup of the illness, which is necessary for understanding the molecular mechanisms or response to therapy. Hence, there is an essential need to create a model that replicates the developmental changes seen in ADHD. Converting human somatic cells into induced pluripotent stem cells (hiPSC) and directing their growth into neuronal cells is an advanced technology that offers the opportunity to create live human neurons for studying complex genetic diseases such neurodevelopmental disorders like ADHD. The main goal of the project is to create a pool of iPSC from patients and controls for studying cellular phenotypes and molecular changes that could cause neurodevelopmental delays.

Growth rates will be evaluated at several developmental phases, such as iPSC and NSC. Neuronal maturation and functionality will also be evaluated, including synapse formation and calcium imaging. The study will evaluate factors believed to be linked to ADHD, such as neuroinflammation and oxidative stress. Central molecular pathways such as as Wnt-signaling will be investigated, known for its broad involvement from development, neurogenesis to neuronal maintenance.

Furthermore, the effects of treatment on the mentioned parameters will be evaluated to comprehend the mechanisms of action of therapies such as the psychostimulant Methylphenidate or the nutritional supplementation of omega-3 fatty acids.

SRF PULS 02.05.2022 Hyperaktivität-Erwachsene unter Dauerstrom staring from 12.47 min

Lucia Dutan Polit, Ilse Eidhof, Rhiannon V. McNeill, Katherine M. Warre-Cornish, Cristine Marie Yde Ohki, Natalie Monet Walter, Carlo Sala, Chiara Verpelli, Franziska Radtke, Silvana Galderisi, Armida Mucci, Ginetta Collo, Frank Edenhofer, Maija L. Castrén, János M. Réthelyi, Morten Ejlersen, Sonja Simone Hohmann, Mirolyuba S. Ilieva, Renate Lukjanska, Rugile Matuleviciute, Tanja Maria Michel, Femke M.S. de Vrij, Steven A. Kushner, Bas Lendemeijer, Sarah Kittel-Schneider, Georg C. Ziegler, Doris Gruber-Schoffnegger, R. Jeroen Pasterkamp, Amal Kasri, Marie-Claude Potier, Jürgen A. Knoblich, Oliver Brüstle, Michael Peitz, Emilio Merlo Pich, Adrian J. Harwood, Elsa Abranches, Anna Falk, Anthony C. Vernon, Edna Grünblatt, Deepak P. Srivastava, Recommendations, guidelines, and best practice for the use of human induced pluripotent stem cells for neuropharmacological studies of neuropsychiatric disorders, Neuroscience Applied, 2023, 101125, ISSN 2772-4085, doi.org/10.1016/j.nsa.2023.101125.

Yde Ohki CM, Walter NM, Rickli M, Van Puyenbroeck P, Döring C, Hoffmann P, Herms S, Maria Werling A, Walitza S, Grünblatt E. Generation of induced pluripotent stem cells from two ADHD patients and two healthy controls. Stem Cell Res. 2023 Mar 27;69:103084. doi:10.1016/j.scr.2023.103084. Yde Ohki CM, Walter NM, Bender A, Rickli M, Ruhstaller S, Walitza S, Grünblatt E. Growth rates of human induced pluripotent stem cells and neural stem cells from attention-deficit hyperactivity disorder patients: a preliminary study. J Neural Transm (Vienna). 2023 Mar;130(3):243-252. doi.org/10.1007/s00702-023-02600-1.

Yde Ohki CM, McNeill RV, Nieberler M, Radtke F, Kittel-Schneider S, Grünblatt E. Promising Developments in the Use of Induced Pluripotent Stem Cells in Research of ADHD. Curr Top Behav Neurosci. 2022;57:483-501. doi:10.1007/7854_2022_346. Yde Ohki CM, Grossmann L, Döring C, Hoffmann P, Herms S, Werling AM, Walitza S, Grünblatt E. Generation of integration-free induced pluripotent stem cells from healthy individuals. Stem Cell Res. 2021 May;53:102269. doi.org/10.1016/j.scr.2021.102269.

Grossmann L, Yde Ohki CM, Döring C, Hoffmann P, Herms S, Werling AM, Walitza S, Grünblatt E. Generation of integration-free induced pluripotent stem cell lines from four pediatric ADHD patients. Stem Cell Res. 2021 May;53:102268. doi:10.1016/j.scr.2021.102268. Filice F, Schwaller B, Michel TM, Grünblatt E. Profiling parvalbumin interneurons using iPSC: challenges and perspectives for Autism Spectrum Disorder (ASD). Mol Autism. 2020 Jan 29;11(1):10. 10.1186/s13229-020-0314-0.

Re S, Dogan AA, Ben-Shachar D, Berger G, Werling AM, Walitza S, Grünblatt E. Improved Generation of Induced Pluripotent Stem Cells From Hair Derived Keratinocytes - A Tool to Study Neurodevelopmental Disorders as ADHD. Front Cell Neurosci. 2018 Sep 25;12:321. doi.org/10.3389/fncel.2018.00321.

Prof. Dr. Edna Grünblatt
Department of Child and Adolescent Psychiatry and Psychotherapy, Psychiatric Hospital University of Zürich
edna.gruenblatt@kjpd.uzh.ch