Astrocytic mechanism of glutamate modulation underlying synchronous bursting in cortical cultures

Abstract

Synchronous bursting (SB) is ubiquitous in neuronal networks. It is known for a long time that SB is driven by glutamatergic neurotransmissions but its underlying mechanism is still unclear. Recent studies show that local glutamate recycle by astrocytes can affect neuronal activities nearby. Since SB is independent of network structure, it is conceivable that the local dynamics might also be the origin of SB in networks. We investigated the effects of local glutamate dynamics on SBs in both cultures developed on multi-electrode array (MEA) systems and a tripartite synapse simulation model. In our experiments, local glutamate recycle dynamics are studied by pharmacologically targeting the astrocytic glutamate transporters (GLT-1), while neuronal firing activities and synaptic glutamate level are simultaneously monitored with MEA and glutamate sensor (iGluSnFR) expressed on surface of astrocytes respectively. We found SBs to be synchronized with glutamate transients and the manipulation of local glutamate dynamics can indeed alter the global properties of the SBs. Detailed simulation of a network with astrocytic glutamate uptake and recycle mechanisms conforming with the experimental observations revealed that astrocytes function as a slow negative feedback for the neuronal activities in the network. With this model, SB can be understood as the alternation between the positive and negative feedback in the neurons and astrocytes in the network respectively. An understanding of this glutamate trafficking dynamics is of general application to explain disordered phenomena in neuronal systems, and therefore can provide new insights into the origin of fatal seizure-like behavior. SignificanceSynchronous bursting (SB) is a hallmark of neuronal circuits. Contrary to the common belief that the SB is governed mainly by neuron-neuron interactions, this study shows that SBs are orchestrated through a generic neuron-astrocyte tripartite interactions. These interactions, identified as glutamate uptake and recycle processes in astrocytes, control the excitability of neuronal networks and shape the overall SB patterns. Our simulation results suggest that astrocytes traffic more glutamate than neurons and actively regulating glutamate proceedings around synapses. A bipartite synapse is a good approximation of a tripartite synapse provided that astrocyte-dependent glutamate content is taken into account. Our findings provide key insights into the ubiquity of SB and the origin of fatal seizure-like behavior in brain arising from astrocytic malfunction.