DOC2B and Munc13-1 differentially regulate neuronal network activity.

Alterations in the levels of synaptic proteins affect synaptic transmission and synaptic plasticity. However, the precise effects on neuronal network activity are still enigmatic. Here, we utilized microelectrode array (MEA) to elucidate how manipulation of the presynaptic release process affects the activity of neuronal networks. By combining pharmacological tools and genetic manipulation of synaptic proteins, we show that overexpression of DOC2B and Munc13-1, proteins known to promote vesicular maturation and release, elicits opposite effects on the activity of the neuronal network. Although both cause an increase in the overall number of spikes, the distribution of spikes is different. While DOC2B enhances, Munc13-1 reduces the firing rate within bursts of spikes throughout the network; however, Munc13-1 increases the rate of network bursts. DOC2B's effects were mimicked by Strontium that elevates asynchronous release but not by a DOC2B mutant that enhances spontaneous release rate. This suggests for the first time that increased asynchronous release on the single-neuron level promotes bursting activity in the network level. This innovative study demonstrates the complementary role of the network level in explaining the physiological relevance of the cellular activity of presynaptic proteins and the transformation of synaptic release manipulation from the neuron to the network level.