In the intact mouse hippocampus patterned afferent stimulation does not lead to long-term depression (LTD) at Schaffer collateral (Sc)-CA1 synapses, but the same synapses express robust LTD (<24 h) if test-pulse or patterned afferent experience is coupled with novel spatial learning. This suggests that the failure of sole afferent stimulation to elicit LTD relates to the absence of neuromodulatory input related to increased arousal or novelty during learning. Locus coeruleus (LC) firing increases during novel experience, and in rats patterned stimulation of the LC together with test-pulse stimulation of Sc-CA1 synapses leads to robust LTD in vivo. This effect is mediated by beta-adrenergic receptors. Here, we explored if activation of beta-adrenergic receptors supports the expression of LTD in freely behaving mice. We also explored if beta-adrenergic receptors contribute to endogenous LTD that is expressed following spatial learning. Patterned stimulation of Sc-CA1 synapses at 3 Hz (200 pulses) resulted in short-term depression (STD). Pretreatment with isoproterenol, an agonist of beta-adrenergic receptors, resulted in robust LTD (<24 h). Test-pulse stimulation under control conditions elicited field potentials that were stable for the 24-h monitoring period. Coupling of test-pulses with a novel spatial object recognition task resulted in robust endogenous LTD (<24 h). Pretreatment with propranolol, a beta-adrenergic receptor antagonist, completely prevented endogenous LTD that was enabled by learning and prevented object recognition learning itself. These data indicate that the absence of LTD in freely behaving mice, under standard recording conditions, does not reflect an inability of mice to express LTD, rather it is due to the absence of a noradrenalin tonus. Our data also support that spatial object recognition requires beta-adrenergic receptor activation. Furthermore, LTD that is enabled by novel spatial learning critically depends on activation of beta-adrenergic receptors that are presumably activated by noradrenalin released by the LC in response to the novel experience. © 2013 Wiley Periodicals, Inc.