Altered network and rescue of human neurons derived from individuals with early-onset genetic epilepsy

• Published in: Molecular psychiatry Vol. 26; no. 11; pp. 7047 - 7068
• Main Authors: Negraes, Priscilla D., Trujillo, Cleber A., Yu, Nam-Kyung, Wu, Wei, Yao, Hang, Liang, Nicholas, Lautz, Jonathan D., Kwok, Ellius, McClatchy, Daniel, Diedrich, Jolene, de Bartolome, Salvador Martinez, Truong, Justin, Szeto, Ryan, Tran, Timothy, Herai, Roberto H., Smith, Stephen E. P., Haddad, Gabriel G., Yates, John R., Muotri, Alysson R.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.11.2021; Nature Publishing Group
• Subjects: 13; 13/1; 13/100; 14; 14/19; 38/39; 38/47; 631/154; 631/378; 631/532; 692/699/476; 82/80; 9/74; 96/106; 96/95; 96/98; Age; Animals; Behavioral Sciences; Binding sites; Biological Psychology; Brain research; Cell cycle; Cell proliferation; Complications and side effects; Convulsions & seizures; Cyclin-dependent kinases; Cytoskeleton; Development and progression; Drug screening; Epilepsy; Epileptic Syndromes - genetics; Gene mutations; Genetic aspects; Genetic disorders; Glutamatergic transmission; Health aspects; Humans; Hyperactivity; Kinases; Medicine; Medicine & Public Health; Mice; Mutation; Neural networks; Neural stem cells; Neurodevelopmental disorders; Neurological research; Neurons; Neurons - metabolism; Neurosciences; Pharmacotherapy; Pluripotency; Progenitor cells; Protein Serine-Threonine Kinases; Proteins; Proteomics; Psychiatry; Seizures; Stem cells; Synaptogenesis; X chromosomes; United States
• ISSN: 1359-4184; 1476-5578
• DOI: 10.1038/s41380-021-01104-2

Early-onset epileptic encephalopathies are severe disorders often associated with specific genetic mutations. In this context, the CDKL5 deficiency disorder (CDD) is a neurodevelopmental condition characterized by early-onset seizures, intellectual delay, and motor dysfunction. Although crucial for proper brain development, the precise targets of CDKL5 and its relation to patients’ symptoms are still unknown. Here, induced pluripotent stem cells derived from individuals deficient in CDKL5 protein were used to generate neural cells. Proteomic and phosphoproteomic approaches revealed disruption of several pathways, including microtubule-based processes and cytoskeleton organization. While CDD-derived neural progenitor cells have proliferation defects, neurons showed morphological alterations and compromised glutamatergic synaptogenesis. Moreover, the electrical activity of CDD cortical neurons revealed hyperexcitability during development, leading to an overly synchronized network. Many parameters of this hyperactive network were rescued by lead compounds selected from a human high-throughput drug screening platform. Our results enlighten cellular, molecular, and neural network mechanisms of genetic epilepsy that could ultimately promote novel therapeutic opportunities for patients.