Astrocytic mechanism of glutamate modulation underlying synchronous bursting in cortical cultures

Synchronous bursting (SB), a collective dynamics of neuronal network, is related to brain functions. Its underlying mechanism still remains unclear. Recent studies provide sufficient evidence that astrocytes participate in synaptic transmissions. However, the role of astrocytes in SB is not yet well understood. Here, we investigated collective dynamics of astrocytes and neurons simultaneously by using cortical cell cultures developed on multi-electrode array (MEA) systems. Employing glutamate sensors (iGluSnFR) specifically expressed on astrocytes, we observed array-wide rapid rise and fall of synaptic glutamate level during SB. These glutamate traffics at synapses are likely responsible for the persistence of neuronal activities for up to seconds. We found that properties of SB events such as bursting rate and burst duration depend on the activities of GLT-1 glutamate transporters, known to majorly express on astrocytes. In addition, through genetically-encoded calcium indicator (GECI), we also observed concomitant array-wide synchronous calcium elevations in astrocytes. By including the glutamate traffics related to astrocytes, a tripartite synapse model (TUMA) was developed to conform with our experimental observations. Simulation results of the TUMA model show that astrocytes regulate synaptic transmissions by fixing the total amount of available glutamate in the pre-synaptic neuron which in turn controls the dynamics of the SB. During SB, the tripartite TUMA synapse is basically a traditional bipartite synapse with the amount of astrocyte-controlled neurotransmitters.