Dopamine D1/D5 receptors gate the acquisition of novel information through hippocampal long-term potentiation and long-term depression

Abstract

Hebbian learning models require that neurons are able to both strengthen and weaken their synaptic connections. Hippocampal synaptic plasticity, in the form of long-term potentiation (LTP) and long-term depression (LTD), has been implicated in both spatial memory formation as well as novelty acquisition. In addition, the ventral tegmental area-hippocampal loop has been proposed to control the entry of information into long-term memory, whereas the dopaminergic system is believed to play an important role in information acquisition and synaptic plasticity. D1/D5 dopamine receptors are positively coupled to adenylyl cyclase and have been to modulate certain forms of synaptic plasticity, particularly in vitro. We investigated how D1/D5 dopamine receptors modify long-lasting synaptic plasticity at CA1 synapses of adult freely moving rats and found that receptor activation lowered the threshold for the induction of both LTP and LTD. Specific types of learning are associated with specific types of hippocampal synaptic plasticity. We found that object-configuration learning, facilitation of late-phase LTD by object exploration, and late-phase LTP by exploration of empty space were all prevented by D1/D5 receptor antagonism. Furthermore, receptor antagonism prevented electrically induced late-LTP, whereas receptor activation facilitated induction of both LTP and LTD by patterned electrical stimulation. These findings suggest that the dopaminergic system, acting via D1/D5 receptors, gates long-term changes in synaptic strength and that these changes are a critical factor in the acquisition of novel information.

Figure 1.

Learning object–place configurations in a large holeboard is dependent on D₁/D₅ receptor activation. Top, The mean number of dips displayed by animals, along with the SEs for each trial and condition are graphed. The number of dips in animals given injections of saline (control) was significantly reduced when the animals were re-exposed to the same object configuration (habituation) (∗∗p < 0.01). Object rearrangement revealed behavior that was not significantly different from the first-time exposure (Exp.) and supports that the animal recognized the novelty of this configuration (new learning) with significant habituation on the second trial (∗∗p < 0.01). The number of dips in the presence of the D₁/D₅ agonist chloro-PB (41.65 μg) was similar to that seen during saline treatment. However, dips in the presence of the D₁/D₅ antagonist SCH 23390 (29.7 μg) were unchanged after re-exposure to the same object configuration. Exposure to the same object configuration for the third time (after drug washout) revealed significantly fewer dips, consistent with a habituation effect. i.c.v., Intracerebroventricular (p < 0.05).

Figure 2.

D₁/D₅ receptor modulates both LTD and LTP at the SC–CA1 synapse. The mean EPSP slope is graphed along with the corresponding SEs. A, 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 (41.65 μg of chloro-PB) or a selective D₁/D₅ antagonist (29.7 μg of SCH 23390). B–D, Insets, Analog traces representing SC–CA1 field potentials before LFS and 4 h after LFS. Calibration: vertical bar, 1 mV; horizontal bar, 3 ms. B, D₁/D₅ receptor activation is necessary for induction of LTD. Application of the antagonist SCH 23390 (29.7 μg) significantly impaired LTD maintenance. C, D₁/D₅ receptors contribute to late stages of LTP. Application of the antagonist SCH 23390 (29.7 μg) prevents expression of LTP beyond ∼3 h post-tetanus. D, D₁/D₅ receptor activation facilitates STD into LTD. Application of the agonist chloro-PB (41.65 μg) before LFS (1 Hz, 600 pulses) results in robust LTD that endures for >4 h. E, D₁/D₅ activation facilitates STP into LTP. Application of the agonist chloro-PB (41.65 μg) before tetanization results in robust LTP (2 trains of 30 pulses at 100 Hz) that endures for >4 h.

Figure 3.

LTD is induced by animal exposure to novel spatial configurations of objects. The mean EPSP slope is graphed along with the corresponding SEs. A, Application of LFS (arrow) induced short-term depression. LFS given simultaneously with holeboard exposure facilitated LTD after first-time exposure, or if the objects were repositioned (object rearrangement). No facilitation occurred after re-exposure to the holeboard containing the same object configuration as in the first exposure. B–E, Analog traces representing SC–CA1 field potentials before LFS, 5 min after LFS, and 4 h after LFS (right to left) in controls (B), where novel holeboard exploration occurred (C), where holeboard re-exposure occurred (D), and where subsequent exposure to the holeboard with novel object configurations occurred (E). Calibration: vertical bar, 1 mV; horizontal bar, 3 ms.

Figure 4.

Antagonism of D₁/D₅ receptors inhibits exploration-induced LTD. The mean EPSP slope is graphed along with the corresponding SEs. A, LFS applied under novel exploration induced LTD when animals were given injections of saline but not when given injections of 29.7 μg of the D₁/D₅ antagonist SCH 23390. B, C, Analog traces illustrate potentials evoked before LFS, 5 min after LFS, and 4 h after LFS (from left to right) under the following conditions: B, control LFS stimulation (top) compared with LFS stimulation with novelty exploration (bottom); C, control LFS stimulation compared with LFS with novelty exploration after D₁/D₅ antagonist administration. Calibration: vertical bar, 1 mV; horizontal bar, 5 ms.

Figure 5.

SCH 23390 inhibits exploration-induced LTP. The mean EPSP slope is graphed along with the corresponding SEs. A, HFS applied under novel exploration induced LTP when animals were given injections of saline but not when given injections of 29.7 μg of the D₁/D₅ antagonist SCH 23390. Analog traces represent control HFS stimulation (B), HFS with novelty exploration (C), and HFS with novelty exploration and D₁/D₅ antagonist administration (D). They illustrate (from left to right) levels before LFS, 5 min after LFS, and 4 h after LFS. Calibration: vertical bar, 1 mV; horizontal bar, 4 ms.