Astrocytes control UP state and slow oscillation periodicity in human cortical networks

Abstract

Astrocytes are well known for homeostatic roles in energy maintenance, neurotransmitter recovery and immunoreactivity, however their contributing role in active modulation of neuronal activity remains controversial. Recent evidence highlights astrocytes as a potential signalling partner in ongoing high-order neuronal activity, and a modulator of baseline activity. Here we utilise an iPSC-derived in vitro cortical network model to describe a slow-wave oscillation and examine the contributions of astrocytes to development of this oscillatory activity, dependant upon generation of UP/DOWN state phenomena. To examine the role of astrocytes we invoke an acetylcholinergic oscillation in the neuronal population by addition of carbachol, which proved to be a robust mechanism for eliciting prolonged and synchronised network bursting. Pharmalogical interrogation determined oscillatory maintenance was dependent on both glutamatergic and purinergic signalling pathways. Upon further interrogation, we determined that astrocytic calcium signalling was essential to timing of the oscillatory signal. By utilising chemogenetic actuators we showed that whilst neurons are essential and sufficient for instigating the oscillatory signal, astrocytes played a key role in timing. This previously unreported mechanism may contribute to initial development of brain activity, and may underlie a basal activity present later during adulthood. In collaboration with recent results highlighting the role of active gliotransmission, this highlights astrocytes as an important research target for understanding brain activity alterations during development and disease.