Dopamine D1/D5, But not D2/D3, Receptor Dependency of Synaptic Plasticity at Hippocampal Mossy Fiber Synapses that Is Enabled by Patterned Afferent Stimulation, or Spatial Learning

Abstract

Although the mossy fiber (MF) synapses of the hippocampal CA3 region display quite distinct properties in terms of the molecular mechanisms that underlie synaptic plasticity, they nonetheless exhibit persistent (>24 h) synaptic plasticity that is akin to that observed at the Schaffer collateral (SCH)-CA1 and perforant path (PP)-dentate gyrus (DG) synapses of freely behaving rats. In addition, they also respond to novel spatial learning with very enduring forms of long-term potentiation (LTP) and long-term depression (LTD). These latter forms of synaptic plasticity are directly related to the learning behavior: novel exploration of generalized changes in space facilitates the expression of LTP at MF-CA3 synapses, whereas exploration of novel configurations of large environmental features facilitates the expression of LTD. In the absence of spatial novelty, synaptic plasticity is not expressed. Motivation is a potent determinant of whether learning about the spatial experience effectively occurs and the neuromodulator dopamine (DA) plays a key role in motivation-based learning. Prior research on the regulation by DA receptors of long-term synaptic plasticity in CA1 and DG synapses in vivo suggests that whereas D2/D3 receptors may modulate a general predisposition toward expressing plasticity, D1/D5 receptors may directly regulate the direction of change in synaptic strength that occurs during learning. Although the CA3 region is believed to play a pivotal role in many forms of learning, the role of dopamine receptors in persistent (>24 h) forms of synaptic plasticity at MF-CA3 synapses is unknown. Here, we report that whereas pharmacological antagonism of D2/D3 receptors had no impact on LTP or LTD, antagonism of D1/D5 receptors significantly impaired LTP and LTD that were induced by solely by means of patterned afferent stimulation, or LTP/LTD that are typically enhanced by the conjunction of afferent stimulation and novel spatial learning. These data indicate an important role for DA acting on D1/D5 receptors in the support of long-lasting and learning-related forms of synaptic plasticity at MF-CA3 synapses and provide further evidence for an important neuromodulatory role for this receptor in experience-dependent synaptic encoding in the hippocampal subfields.

Keywords: CA3; D1/D5; D2/D3; dopamine; in vivo; learning; mossy fibers; synaptic plasticity.

Figure 1

The D1/D5 receptor antagonist SCH23390 and the D2/D3-receptor antagonist remoxipride have no effect on basal synaptic transmission. (A,B) In vehicle-injected animals, test-pulse stimulation evoked stable field excitatory postsynaptic potential (fEPSP) responses for the duration of the monitoring period. Injection of the D1/D5 receptor antagonist (A) or the D2/D3-receptor antagonist remoxipride (B) had no effect on evoked responses. Line breaks indicate change in time scale. (C) Analog responses were obtained during a control experiment (open circle) and during an SCH23390 experiment (filled circle); (i) pre-injection; (ii) post-injection; and (iii) 24 h post-injection. Vertical scale bar: 1 mV, horizontal scale bar: 10 ms. (D) Analogs depict traces recorded from animal in control experiments (open circle), during an experiment with 50 μg Remoxipride (filled circle) and 100 μg Remoxipride (open triangle); (i) pre-injection; (ii) post-injection; and (iii) 24 h post-injection. Vertical scale bar: 1 mV, horizontal scale bar: 10 ms.

Figure 2

The D2/D3-receptor antagonist remoxipride does not affect long-term plasticity at mossy fiber (MF)-CA3 synapses. (A,B) Vehicle-treated animals that received low-frequency stimulation (LFS, 1 Hz, 900 pulses) showed robust long-term depression (LTD) that lasted for over 25 h. LFS in the presence of remoxipride in the doses of 50 μg (A) or 100 μg (B) expressed long-term potentiation (LTP) that was not significantly different from controls. (C,D) Analogs from an LTD experiment that show responses recorded in vehicle-treated animals (open circle) and in animal treated with Remoxipride at a dose of 50 μg (C) or 100 μg (D; filled circle); (i) pre-LFS; (ii) post-LFS; and (iii) 24 h post-LFS. (E,F) High-frequency stimulation (HFS, 4 × 100 pulses at 100 Hz) resulted in robust LTP in vehicle-treated controls, that was unchanged by treatment of the animals with remoxipride in the doses of 50 μg (E) or 100 μg (F). Line breaks indicate change in time scale. (G,H) Analogs from an LTP experiment that show responses recorded in vehicle-treated animals (open circle) and in animal treated with remoxipride at a dose of 50 μg (G) or 100 μg (H; filled circle); (i) pre-HFS; (ii) post-HFS; and (iii) 24 h post-HFS. Vertical scale bar: 1 mV, horizontal scale bar: 10 ms.

Figure 3

Antagonism of D1/D5-receptors inhibits synaptic plasticity at MF-CA3 synapses. (A) LFS (1 Hz, 900 pulses) results in LTD in vehicle-treated animals. LFS in the presence of SCH23390 (30 μg) significantly prevents LTD at MF-CA3 synapses. (B) HFS (four trains of 100 pulses at 100 Hz) elicits LTP at MF-CA3 synapses of vehicle-treated animals, whereas antagonism of D1/D5 receptors (SCH23390, 30 μg) significantly prevents LTP. Line breaks indicate change in time scale. (C) Analog traces depict fEPSPs recorded at MF-CA3 synapses during an LTD experiment in control animals (open circle) and SCH23390-treated animals (filled circle); (i) pre-LFS; (ii) post-LFS; and (iii) 24 h post-LFS. Vertical scale bar: 1 mV, horizontal scale bar: 10 ms. (D) Analog traces depict fEPSPs recorded at MF-CA3 synapses during an LTP experiment; (i) pre-HFS; (ii) post-HFS; and (iii) 24 h post-HFS in the presence of vehicle (open circle) or SCH23390 (filled circle). Vertical scale bar: 1 mV, horizontal scale bar: 10 ms.

Figure 4

Antagonism of D1/D5 receptors inhibits learning-facilitated plasticity at MF-CA3 synapses. (A) Weak low-frequency stimulation (wLFS; 1 Hz, 600 pulses) results in short-term depression (STD) in vehicle-treated animals. Upon first exposure to landmark cues, application of wLFS also resulted in STD in animals that were treated with SCH23390 (30 μg). A second exposure (re-exposure) to the same object-place constellations 1 week later resulted in LTD. When the animals explored the cues for a third time (a further week later), wLFS failed to result in LTD. (B) Weak high-frequency stimulation (wHFS, two trains of 100 pulses given at 100 Hz) results in STP in vehicle-treated animals. The first (novel) exposure of the animals to an empty holeboard results in short-term potentiation (STP) in animals that received SCH23390 (30 μg). A second exposure to the same holeboard 1 week later, leads to a facilitation of LTP that lasts for over 24 h. wHFS given during a third exposure to the same holeboard results in STP. Line breaks indicate change in time scale. (C) Analogs represent fEPSP responses obtained in an LTD experiment where a vehicle-treated animal received wLFS only (open circle), and Schaffer collateral (SCH)-treated animal explored the novel cues for the first time (filled circle), an animal that we exposed to the cues for a 2nd time (open triangle) or a 3rd time (filled square). The following time-points are shown: (i) pre-wLFS; (ii) post-wLFS; and (iii) 24 h post-wLFS. (D) Analogs represent fEPSP responses obtained in an LTP experiment where a vehicle-treated animal received wHFS only (open circle), and SCH-treated animal explored the novel cues for the first time (filled circle), an animal that we exposed to the cues for a 2nd time (open triangle) or a 3rd time (filled square). The following time-points are shown: (i) pre-wHFS; (ii) post-wHFS; and (iii) 24 h post-wHFS. Vertical scale bar: 1 mV, horizontal scale bar: 10 ms.