Abstract
The electrical activity of the brain arises from single neurons communicating with each other. However, how single neurons interact during early development to give rise to neural network activity remains poorly understood. We studied the emergence of synchronous neural activity in human pluripotent stem cell (hPSC)-derived neural networks simultaneously on a single-neuron level and network level. The contribution of gamma-aminobutyric acid (GABA) and gap junctions to the development of synchronous activity in hPSC-derived neural networks was studied with GABA agonist and antagonist and by blocking gap junctional communication, respectively. We characterized the dynamics of the network-wide synchrony in hPSC-derived neural networks with high spatial resolution (calcium imaging) and temporal resolution microelectrode array (MEA). We found that the emergence of synchrony correlates with a decrease in very strong GABA excitation. However, the synchronous network was found to consist of a heterogeneous mixture of synchronously active cells with variable responses to GABA, GABA agonists and gap junction blockers. Furthermore, we show how single-cell distributions give rise to the network effect of GABA, GABA agonists and gap junction blockers. Finally, based on our observations, we suggest that the earliest form of synchronous neuronal activity depends on gap junctions and a decrease in GABA induced depolarization but not on GABAA mediated signaling.
Highlights
A better understanding of the human brain and its development would allow us to answer questions such as how the brain functions, how the brain malfunctions, and how the brain can be cured
We showed that the single-neuron excitatory response to GABA decreases as neurons start to participate in synchronous network activity
We showed that gap junctionmediated connections modulate the interval between events, allowing network events to occur more frequently
Summary
A better understanding of the human brain and its development would allow us to answer questions such as how the brain functions, how the brain malfunctions, and how the brain can be cured. The nature and function of the human brain remains to be fully understood. The electrical activity of the brain arises from single neurons communicating with each other. Groups of communicating neurons form neural networks, which function as the computing hubs of the brain. How single neurons give rise to neural network activity remains poorly understood. Patterned neural network activity arises when asynchronous neurons self-organize their firing patterns into synchronous activity (for review Corlew et al, 2004; Blankenship and Feller, 2010; Kerschensteiner, 2014; Luhmann et al, 2016).
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