Dopamine D1/D5 receptors mediate informational saliency that promotes persistent hippocampal long-term plasticity

Abstract

Dopamine (DA) plays an essential role in the enablement of cognition. It adds color to experience-dependent information storage, conferring salience to the memories that result. At the synaptic level, experience-dependent information storage is enabled by synaptic plasticity, and given its importance for memory formation, it is not surprising that DA comprises a key neuromodulator in the enablement of synaptic plasticity, and particularly of plasticity that persists for longer periods of time: Analogous to long-term memory. The hippocampus, that is a critical structure for the synaptic processing of semantic, episodic, spatial, and declarative memories, is specifically affected by DA, with the D1/D5 receptor proving crucial for hippocampus-dependent memory. Furthermore, D1/D5 receptors are pivotal in conferring the properties of novelty and reward to information being processed by the hippocampus. They also facilitate the expression of persistent forms of synaptic plasticity, and given reports that both long-term potentiation and long-term depression encode different aspects of spatial representations, this suggests that D1/D5 receptors can drive the nature and qualitative content of stored information in the hippocampus. In light of these observations, we propose that D1/D5 receptors gate hippocampal long-term plasticity and memory and are pivotal in conferring the properties of novelty and reward to information being processed by the hippocampus.

Keywords: cognition; hippocampus; learning and memory; review; synaptic plasticity.

Figure 1.

Signal cascades of D1 and D5 receptors. Schematic demonstration of the different molecular pathways of D1 (yellow boxes) and D5 receptors (blue boxes) ending in a common CREB activation (gray boxes). Crosstalk between the D1/D5 system is indicated by red dashed lines. An inhibitory effect is signified by a circle containing a minus symbol. Abbreviations: AC: adenylcyclase; AktP: Akt phosphorylated; CaMKII: calcium–calmodulin-dependent protein kinase type II; cAMP: cyclic 3′5′ adenosine monophosphate; CRE: cAMP response element; CREB: cAMP response element-binding protein; CREB P: CREB phosphorylated; DARPP-32: phosphoprotein of 32 kDa; DGL: diacylglycerol; D1: dopamine receptor 1; D5: dopamine receptor 5; EPAC: exchange protein activated by cAMP; ERK: extracellular signal-regulated kinase; G-p: G protein; IP3: inositol trisphosphate (IP3); by cAMP; ERK: extracellular signal-regulated kinase; MEK's: mitogen-activated kinases; PDK1: phosphoinositide-dependent kinase-1; PIP 2: phosphatidylinositol-4;5-bisphosphate; PIP3: phosphatidylinositol-3;4;5-triphosphate; PI3K: phosphatidylinositol-3-kinase; PKA: protein kinase A; PKC: protein kinase C; PLC: phospholipase C; PPtase 1: protein phosphatase 1; RAP 1: member of the RAS family of small GTP-binding proteins (Undieh 2010; Beaulieu and Gainetdinov 2011).

Figure 2.

Anatomical connections between the hippocampus and dopaminergic nuclei. The VTA, retrorubral field (RRF), and LC all send projections to the hippocampus (HPC). The hippocampus in turn projects, on the one hand, to the NAcc that is connected with the VTA (hippocampal–VTA loop) and substantia nigra (SN) by the VP. On the other hand, the hippocampus projects to the peduncolopontine tegmentum (PPTg) that sends projections to the VTA and SN. Additionally, the PFC sends and receives projections from the hippocampus.

Figure 3.

Regulation of hippocampal synaptic plasticity by the VTA and other dopaminergic nuclei. The dopaminergic regulation of hippocampal synaptic plasticity and the underlying network is depicted here. Blue arrows indicate the novelty activated VTA–hippocampal loop. The novelty signal is mediated from the perirhinal cortex (PERI) to the enthorinal cortex (EC). Additionally, the EC conveys object and space information to the DG and CA1. Here, the information is integrated to “object-in-context” representations and then processed via the NAcc and VP as the descending arc of the hippocampal–VTA loop to the VTA. The gray and black arrows show the different projections between the dopaminergic brainstem nuclei and the brain structures referring to the hippocampus and VTA involved in the dopaminergic modulation of hippocampal synaptic transmission. The gray dashed line indicates the separation of the cerebrum and brainstem. An inhibitory projection is indicated by a circle containing a minus symbol and an excitatory projection is indicated by a circle combined with a plus symbol. In this figure not all, but rather the main connections are shown. Abbreviations: EC: entorhinal cortex, LC: locus coeruleus, L2/3: layer 2/3 of the EC, MF: mossy fibers, NAcc: nucleus accumbens, PARA: parahippocampus, PERI: perirhinal cortex, PP: perforant path, SC: Schaffer collaterals, SUB: subiculum, TA: temporoammonic pathway, VP: ventral palladium, VTA: ventral tegmental area. (Simon et al. 1979; Grace 1991; Howland et al. 2002; Lisman and Grace 2005; Yin et al. 2008; Sara 2009; Lisman et al. 2011).