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

Abstract

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.

Figure 1.

The dopamine D1/D5 ligands do not affect basal synaptic transmission at the concentrations tested. SC-CA1 synaptic transmission was stable in vehicle-injected animals throughout the recording period. Basal synaptic transmission was not significantly affected by intracerebroventricular injection of a selective D1/D5 agonist (42 μg of chloro-PB) or a selective D1/D5 antagonist (30 μg of SCH23390).

Figure 2.

Exposure to the novel holeboard in the presence of test-pulse stimulation of CA1 afferents enables STD. SC-CA1 synaptic strength was not significantly altered after 10 min of holeboard exploration in vehicle-treated animals. Vehicle was applied 30 min prior to exposure to the holeboard (signified by arrow). Test pulses delivered during holeboard exploration detected STD at SC-CA1 synapses during the first 5 min of exploration. In the absence of test-pulse stimulation, an STD occurred following spatial exploration. Insets: Analog traces representing SC-CA1 field potentials during 1) baseline, 2) holeboard exploration, and 3) 4 h after holeboard exploration. Calibration: vertical bar, 1 mV; horizontal bar, 3 ms.

Figure 3.

Holeboard habituation is prevented by antagonism of D1/D5 receptors. Analysis of rearing (A) and dipping (B) behavior during exposure to the novel and familiar object–place configurations demonstrated that whereas vehicle-treated animals (n = 6) exhibited habituation to the object–place configuration (second exposure, 7 days after first exposure), animals treated with the D1/D5 antagonist SCH23390 (30 μg, n = 6) did not habituate. A third exposure to the same object–place configuration, 7 days after the second exposure, revealed habituation behavior in both the control and the antagonist-treated groups.

Figure 4.

Treatment with a D1/D5 agonist in the presence of a novel holeboard elicits slow-onset depression. Learning-facilitated LTD is unaffected. (A) SC-CA1 synaptic strength was not significantly altered following holeboard exploration in the absence of test-pulse stimulation. In contrast, holeboard exploration in the absence of test-pulse stimulation but in the presence of a selective D1/D5 agonist (42 μg of chloro-PB), resulted in slow-onset depression lasting >4 h. Insets: Analog traces represent SC-CA1 field potentials during baseline, 15 min, and 4 h after holeboard exploration. Calibration: vertical bar, 1 mV; horizontal bar, 3 ms. (B) LFS of SCs (LFS, 1 Hz, 600 pulses) resulted in STD that lasted for approximately 2 h. When LFS was given concurrently with novel exploration of the object-containing holeboard, STD was facilitated into LTD that lasted for over 24 h. Application of the D1/D5 agonist (chloro-PB, 42 μg, n = 8) had no effect on the profile of learning-facilitated LTD elicited.

Figure 5.

LTD mediated by costimulation of the LC and CA1 region is prevented by a D1/D5 antagonist. LC stimulation coupled with novel spatial exploration results in CA1 LTD that lasts for approximately 4 h and is extended >24 h by treatment with a D1/D5 agonist. (A) LC burst stimulation (100 Hz) coupled with test-pulse stimulation of SC-CA1 synapses induces CA1 LTD that lasts for over 4 h. The D1/D5 receptor antagonist, SCH23390 (30 μg), blocks LC stimulation–induced SC-CA1 LTD. Analog traces represent SC-CA1 field potentials during baseline, 15 min, and 4 h after holeboard exploration. Calibration: vertical bar, 1 mV; horizontal bar, 3 ms. (B) LC activation (100 Hz) followed by test-pulse stimulation of CA1 afferents results in LTD that lasts for >4 h (see Fig. 5). Combining novel spatial exploration with LC stimulation did not change the profile of LTD elicited in the CA1 region (n = 8). However, application of the D1/D5 agonist chloro-PB (42 μg) resulted in LTD that lasts for >24 h (n = 8).