Astrocytic Regulation of Synchronous Bursting in Cortical Cultures: From Local to Global

Synchronous bursting (SB) is ubiquitous in neuronal networks and independent of network structure. Although it is known to be driven by glutamatergic neurotransmissions, its underlying mechanism remains unclear. Recent studies show that local glutamate recycle by astrocytes affects nearby neuronal activities, which indicate that the local dynamics might also be the origin of SBs in networks. We investigated the effects of local glutamate dynamics on SBs in both cultures developed on multielectrode array (MEA) systems and a tripartite synapse simulation. Local glutamate uptake by astrocytes was altered by pharmacological targeting of GLT-1 glutamate transporters, whereas neuronal firing activities and synaptic glutamate level was simultaneously monitored with MEA and astrocyte-specific glutamate sensors (intensity-based glutamate-sensing fluorescent reporter), respectively. Global SB properties were significantly altered on targeting GLT-1. Detailed simulation of a network with astrocytic glutamate uptake and recycle mechanisms, conforming with the experimental observations, shows that astrocytes function as a slow negative feedback to neuronal activities in the network. SB in the network can be realized as an alternation between positive and negative feedback in the neurons and astrocytes, respectively. An understanding of glutamate trafficking dynamics is of general application to explain how astrocyte malfunction can result in pathological seizure-like phenomena in neuronal systems.