The molecular and cellular processes controlling the rapid change among different sleep-wakefulness stages in mammals are not fully clear. Although the sleep-relevant neuromodulators have been shown to alter membrane properties and thus firing patterns of thalamic neurons, their modulatory effect on thalamic synaptic transmission is less noted. At the retinogeniculate synapse that shows characteristic short-term synaptic depression (paired-pulse ratio of 0.33±0.08, n=15), we investigated the modulatory effect of combined neuromodulators mimicking different sleep-wakefulness states. The whole brain from the C57/Bl6 mouse (p21-30) was rapidly removed under 1-3% isoflurane inhalation anesthesia, and brain slices containing the retinogeniculate synapse were freshly prepared. We examined the effect of serotonin plus acetylcholine to mimic the awake state (in which the concentration of adenosine should be very low) and the effect of adenosine plus acetylcholine to mimic the paradoxical (rapid eye movement, or REM) sleep state (in which monoamine level is decreased to almost zero). We found that bath application of both 10 nM 5-carboxytryptamine (5-CT, the 5-HT1 receptor agonist) and 3 μM (+)-anabasine (ABS, the nicotinic receptor agonist) or of both 10 μM N6-cyclopentyladenosine (CPA, a potent and selective adenosine A1 receptor agonist) and 3 μM ABS results in similar-size postsynaptic AMPA receptor currents in response to paired-pulse stimulation (separated by 50 ms) of the optic tract. The paired-pulse ratio is 1.09±0.11 (n=5) and 0.88±0.14 (n=6) for the former and the latter combinations, respectively. Moreover, paired stimulation separated by ISIs of a wide range (20-2000 ms) always evokes second EPSC amplitude similar to the first EPSC in the presence of the foregoing combinations of neuromodulators. We further examined the EPSCs in response to a 10 Hz- or 50 Hz-train of 30-stimuli. In control, the postsynaptic currents are more reliably elicited by the earlier than by the later, and by 10 Hz- than 50 Hz-train of, stimuli. This is consistent with an actual “low-pass” transmission through a synapse with short-term depression. In contrast, the elicited synaptic currents all become relatively similar in amplitude in response to either 10 Hz or 50 Hz-train of stimuli and to either earlier or later stimuli in a train in the presence of both nicotinic and adenosine receptor agonists. Thus, short-term plasticity at the retinogeniculate synapse could be essentially abolished over a wide frequency range of presynaptic activity in both awake and paradoxical sleep states. These properties are consistent with a more faithful relay of sensory information through the thalamus during wakefulness and REM sleep, and provide a partial explanation for why we need both serotonin and acetylcholine during wakefulness.