The locus coeruleus (LC) is the primary source of norepinephrine in the brain and is known to modulate brain-wide arousal state. Recent evidence suggests that it also regulates immediate attentional responses by modulating the gain or reset of downstream cortical networks to optimize behavioral outcomes. Accordingly, cortical regions of high cognitive function, such as the medial prefrontal cortex (mPFC), are thought to directly influence LC output for this purpose. However, physiological evidence for monosynaptic connections between mPFC and LC neurons and their properties are still limited. To provide further comprehensive data on this issue, we combined whole-cell recording with an optogenetic approach to study the synaptic transmission of mPFC inputs to LC neurons. We found that 63% of recorded LC neurons responded to optogenetic activation of the mPFC with activation of both AMPA and NMDA receptors. Application of picrotoxin and strychnine did not significantly affect synaptic activity, suggesting that local inhibitory pre-LC neurons were not recruited. In current-clamp recordings, photostimulation of mPFC inputs that mimicked mPFC neuron firing under physiological conditions (600 pseudo-random pulses at 2 Hz) significantly increased the variance of inter-spike-interval but not the mean frequency of LC firing. Interestingly, there was an associated and significant increase in the frequency of spontaneous synaptic events during this photostimulation paradigm, suggesting that mPFC-LC synapses also exhibit asynchronous release. In conclusion, we report here that under physiological conditions, activation of the mPFC can significantly alter the output pattern, without affecting the output strength, of LC neurons by increasing synaptic noise.