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The plasticity of the brain plays a key role in shaping our behavior, learning and memory. It is well known that plasticity is associated with alteration in synaptic strength and efficacy. Some of these effects correlate with changes in the levels of synaptic proteins. However, the implications of genetic alteration in synaptic proteins on the network activity of neurons are not known. We examine the effect of DOC2B, a synaptic neuronal Ca2+ sensor that is known for its ability to enhance synaptic transmission, on neuronal network activity. For that purpose we use MicroElectrode Array (MEA) technology to simultaneously record action potentials from multiple neurons in ex vivo neuronal network. Networks grown on MEA plates exhibit a repeated pattern of synchronized network-wide spiking activity (network burst) separated by periods of reduced activity. At the single-neuron level, DOC2B increased the frequency of spontaneous neurotransmitter release. However, its effect at the network level was restricted to the network bursts and was reflected as an increase in the number of spikes and the number of active neurons throughout the network burst, while surprisingly there was no effect on inter-burst spiking activity. In addition, DOC2B enhanced the number of full-blown network bursts, suggesting an impact on the input/output ratio of synaptic transmission. Further analysis suggested DOC2B’s activity was augmented during neuronal bursts and enhanced spontaneous and asynchronous release. This can increase the neuron’s sensitivity to incoming EPSPs and the number of spikes in the network burst. Additionally, our experiments support the hypothesis that DOC2B efficiently enhances synaptic refilling. Hence, this work shows that the changes at the network level complemented our knowledge on the cellular activity of DOC2B and suggests a role for DOC2B in shaping the firing properties of highly active neuronal networks.