Electrophysiological measures from human iPSC-derived neurons are associated with schizophrenia clinical status and predict individual cognitive performance

Abstract

Neurons derived from human induced pluripotent stem cells (hiPSCs) have been used to model basic cellular aspects of neuropsychiatric disorders, but the relationship between the emergent phenotypes and the clinical characteristics of donor individuals has been unclear. We analyzed RNA expression and indices of cellular function in hiPSC-derived neural progenitors and cortical neurons generated from 13 individuals with high polygenic risk scores (PRSs) for schizophrenia (SCZ) and a clinical diagnosis of SCZ, along with 15 neurotypical individuals with low PRS. We identified electrophysiological measures in the patient-derived neurons that implicated altered Na+ channel function, action potential interspike interval, and gamma-aminobutyric acid–ergic neurotransmission. Importantly, electrophysiological measures predicted cardinal clinical and cognitive features found in these SCZ patients. The identification of basic neuronal physiological properties related to core clinical characteristics of illness is a potentially critical step in generating leads for novel therapeutics.

Human-Induced Pluripotent Stem Cell Technology: Toward the Future of Personalized Psychiatry

“…Finally, Page [ 50 ] identified electrophysiological measures in SZ-iPSC-derived neurons that associate with diagnosis and/or predict the severity of clinical and cognitive features of the adult SZ donor.…”

“…This approach supports the neurodevelopmental hypothesis of SZ, stating that the disruption of early brain development increases the risk of later manifest psychotic symptoms. Patient-derived iPSCs have proven to be a powerful tool in identifying SZ early neurodevelopmental defects, having revealed alterations in neuronal differentiation [ 45 , 48 , 49 ], migration capacity [ 39 , 43 ], neurite number and length [ 38 , 66 ], synaptic biology [ 47 , 49 , 50 ], connectivity [ 38 ], and neuronal activity [ 41 , 42 , 50 ].…”

A microcarrier-based protocol for scalable generation and purification of human induced pluripotent stem cell-derived neurons and astrocytes

“…With respect to neurons, their cellular identity can be confirmed using immunofluorescence analysis for expression of NEUN, MAP2, and TUJ1 whereas their functional properties can be assessed with calcium imaging. However, as described by us and others numerous additional assays can be employed such as Western blotting, transcriptomic analysis, microelectrode array (MEA) analysis, and patch clamp electrophysiology ( Autar et al., 2022 ; Burke et al., 2020 ; Hyvarinen et al., 2019 ; Lin et al., 2016 ; Page et al., 2022 ). Along similar lines, with regards to purified astrocyte cultures we provide methods to assess their identity and functionality using immunofluorescence, flow cytometry, ELISA, and calcium imaging.…”

Monozygotic twins discordant for schizophrenia differ in maturation and synaptic transmission

“…A significant delay in the reduction of endogenous OCT4 and NANOG expression was shown during differentiation in the schizophrenia lines. Na + channel function and GABA-ergic neurotransmission have recently been shown to be altered in neurons derived from iPSCs of schizophrenia patients 34 . These new approaches to neuropsychiatry disorders have the potential to address the problem of brain inaccessibility by providing the investigators with specific neurons of patients with proper diagnostic validity (or simply proper diagnoses).…”