Electrophysiological Properties of Human Cortical Organoids: Current State of the Art and Future Directions.

Clara Zourray,Manju A Kurian,Gabriele Lignani,Serena Barral

doi:10.3389/fnmol.2022.839366

Abstract

Human cortical development is an intricate process resulting in the generation of many interacting cell types and long-range connections to and from other brain regions. Human stem cell-derived cortical organoids are now becoming widely used to model human cortical development both in physiological and pathological conditions, as they offer the advantage of recapitulating human-specific aspects of corticogenesis that were previously inaccessible. Understanding the electrophysiological properties and functional maturation of neurons derived from human cortical organoids is key to ensure their physiological and pathological relevance. Here we review existing data on the electrophysiological properties of neurons in human cortical organoids, as well as recent advances in the complexity of cortical organoid modeling that have led to improvements in functional maturation at single neuron and neuronal network levels. Eventually, a more comprehensive and standardized electrophysiological characterization of these models will allow to better understand human neurophysiology, model diseases and test novel treatments.

Highlights

The human cerebral cortex remains mostly inaccessible for direct functional investigation
This cortical organoid model was used to investigate changes in network activity in organoids derived from patients with CDLK5-deficiency disorder (CDD), a neurodevelopmental disorder associated with early-onset epilepsy (Olson et al, 2019; Negraes et al, 2021)
Cortical organoids exhibit some degree of functional maturation at the cellular and network-level

Summary

INTRODUCTION

The human cerebral cortex remains mostly inaccessible for direct functional investigation. Astrocytes generated in the hCS model were found to closely resemble primary in vivo human astrocytes in terms of their transcriptional signatures They were functionally able to fulfill the same roles of astrocytes in vivo, including glutamate uptake via specific excitatory amino acid transporters, phagocytosis of synaptosomes and induction of synapse formation, important for cortical development and proper network activity (Sloan et al, 2017). Over the course of 10 months, cortical organoids exhibited a steady increase in firing rate, burst frequency, synchronicity and population spiking This cortical organoid model was used to investigate changes in network activity in organoids derived from patients with CDLK5-deficiency disorder (CDD), a neurodevelopmental disorder associated with early-onset epilepsy (Olson et al, 2019; Negraes et al, 2021). MEA recordings showed consistent increases in electrical activity in CDD-derived cortical organoids compared to controls, as well as a significant increase in mean

Results

Findings

DISCUSSION