Dopamine D1/D5 receptors contribute to de novo hippocampal LTD mediated by novel spatial exploration or locus coeruleus activity.

The neurons of the locus coeruleus (LC) fire in response to novelty, and LC activation coupled with hippocampal afferent stimulation leads to long-term depression (LTD). The encoding of novel spatial information also involves activation of dopamine D1/D5 receptors. It is unclear if, or how, the noradrenergic and dopaminergic systems interact mechanistically in processing novelty. Novel spatial exploration when coupled with Schaffer collateral (SC) test-pulse stimulation results in short-term depression at SC-CA1 synapses, which is not observed in the absence of afferent stimulation. However, activation of D1/D5 receptors under these conditions without concomitant afferent stimulation enables slow-onset depression. LTD (>24 h) is facilitated when novel exploration occurs concurrently with low-frequency stimulation of CA1. Effects are not improved by a D1/D5 agonist. Facilitation of LTD (>4 h) by coupling LC stimulation with CA1 test-pulse stimulation was blocked by a D1/D5 antagonist, however, as was habituation to the holeboard environment. Novel spatial learning during LC stimulation did not enhance LTD further, whereas D1/D5 agonist treatment enabled LTD to persist for over 24 h. These data suggest that the regulation of hippocampal LTD by the LC is supported by D1/D5 receptors and that their contribution to information storage becomes important when the thresholds for persistent LTD have not been reached.