Neuronal hyperexcitability and ion channel dysfunction in CDKL5-deficiency patient iPSC-derived cortical organoids

Wei Wu; Hang Yao; Priscilla D. Negraes; Juan Wang; Cleber A. Trujillo; Janaina S. de Souza; Alysson R. Muotri; Gabriel G. Haddad

Neurobiology of Disease (Nov 2022)

Neuronal hyperexcitability and ion channel dysfunction in CDKL5-deficiency patient iPSC-derived cortical organoids

Wei Wu,
Hang Yao,
Priscilla D. Negraes,
Juan Wang,
Cleber A. Trujillo,
Janaina S. de Souza,
Alysson R. Muotri,
Gabriel G. Haddad

Affiliations

Wei Wu: Department of Pediatrics, School of Medicine, University of California San Diego, La Jolla, CA, USA
Hang Yao: Department of Pediatrics, School of Medicine, University of California San Diego, La Jolla, CA, USA
Priscilla D. Negraes: Department of Pediatrics, School of Medicine, University of California San Diego, La Jolla, CA, USA
Juan Wang: Department of Pediatrics, School of Medicine, University of California San Diego, La Jolla, CA, USA
Cleber A. Trujillo: Department of Pediatrics, School of Medicine, University of California San Diego, La Jolla, CA, USA
Janaina S. de Souza: Department of Pediatrics, School of Medicine, University of California San Diego, La Jolla, CA, USA
Alysson R. Muotri: Department of Pediatrics, School of Medicine, University of California San Diego, La Jolla, CA, USA; Department of Cellular & Molecular Medicine, Stem Cell Program, Center for Academic Research and Training in Anthropogeny (CARTA), Archealization Center (ArchC), Kavli Institute for Brain and Mind, University of California San Diego, La Jolla, CA, USA; Corresponding authors at: Department of Pediatrics, School of Medicine, University of California San Diego, La Jolla, CA, USA.
Gabriel G. Haddad: Department of Pediatrics, School of Medicine, University of California San Diego, La Jolla, CA, USA; Department of Neurosciences, University of California San Diego School of Medicine, La Jolla, CA, USA; Rady Children's Hospital, San Diego, CA, USA; Corresponding authors at: Department of Pediatrics, School of Medicine, University of California San Diego, La Jolla, CA, USA.

Journal volume & issue: Vol. 174
p. 105882

Abstract

Read online

Early epilepsy is a prominent feature in patients with CDKL5-deficiency disorder (CDD). The underlying mechanism for excessive excitability in CDD is largely unknown. The brain organoid model has been recently developed to resemble many critical features of early human brain development. Here, we used a brain organoid model to investigate the cellular electrophysiological basis for hyper-excitability in CDD patients. Our study employed cortical organoids derived from two CDD patients harboring the same CDKL5 mutation (R59X) and two controls from their healthy parents. Whole-cell patch-clamp recordings revealed higher action potential (AP) firing rate and lower rheobase in both CDD organoids, indicating increased intrinsic neuronal excitability. We further found dysfunction of voltage-gated ion channels in CDD neurons that leads to hyperexcitability, including higher Na+ and K+ current densities and a negative shift in Na+ channel activation. In contrast to neuronal properties, we found that glutamatergic neurotransmission and the electrophysiological properties of glial cells were not altered in CDD organoids. In support of our CDD findings, we further discovered similar electrophysiologic properties in cortical organoids derived from a Rett syndrome (RTT) patient, including alterations in AP firings and Na+ and K+ channel function suggesting a convergent mechanism. Together, our study suggests a critical role of intrinsic neuronal hyperexcitability and ion channel dysfunction, seen in early brain development in both CDD and RTT disorders. This investigation provides potential novel drug targets for developing treatments of early epilepsy in such disorders.

Published in Neurobiology of Disease

ISSN: 0969-9961 (Print); 1095-953X (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Medicine: Internal medicine: Neurosciences. Biological psychiatry. Neuropsychiatry
Website: https://www.journals.elsevier.com/neurobiology-of-disease

About the journal

Abstract

Keywords