Cognitive processing in the central nervous system relies on accurate information propagation; neurotransmission is the fundamental mechanism underlying network information flow. Because network information is coded by the timing and the strength of neuronal activity, synaptic properties that translate neuronal activity into synaptic output profoundly determine the precision of information transfer. Synaptic properties are in turn shaped by changes in network activity to ensure appropriate synaptic output. Activity-dependent adjustment of synaptic properties is often initiated by second messenger signals. Understanding how second messengers sculpt synaptic properties and produce changes in synaptic output is key for elucidating the interplay between network activity and synaptic properties. We studied the effect of second messenger modification on activity-dependent and static properties of rat hippocampal excitatory synapses using electrophysiological and optical approaches. We focused on two second-messenger pathways that potentiate transmission: cAMP and diacyl glycerol: DAG) signals. In parallel, we also compared the effects of manipulating calcium influx, which is known to potentiate synaptic transmission through increasing release probability: Pr). During high frequency stimulation, we found that both cAMP and DAG signals potentiated phasic transmission, as previously characterized. In parallel with increasing phasic transmission, the modulators also enhanced high-frequency associated asynchronous transmission, which emerges late during stimulus trains and is relatively long-lasting. However, such parallel potentiation of phasic and asynchronous transmission was not seen in elevated calcium; high calcium preferentially promoted asynchronous transmission. With low frequency stimulation, we found that cAMP and high calcium enhanced synaptic output by potentiating synapses with basally high Pr. Conversely, DAG signals recruited neurotransmission from both high Pr and low Pr terminals, which include presynaptically quiescent synapses. Taken together, these results suggest that second messenger modulation of synapses differentially shapes the static properties of the synapses; second messengers also fine-tune activity-dependent synaptic responses differently from manipulating calcium influx. These results likely have physiological relevance to second messenger-dependent sculpting of temporal and spatial synaptic properties
