Cellular signal mechanisms of reward-related plasticity in the hippocampus

Abstract

The hippocampus has the extraordinary capacity to process and store information. Consequently, there is an intense interest in the mechanisms that underline learning and memory. Synaptic plasticity has been hypothesized to be the neuronal substrate for learning. Ca(2+) and Ca(2+)-activated kinases control cellular processes of most forms of hippocampal synapse plasticity. In this paper, I aim to integrate our current understanding of Ca(2+)-mediated synaptic plasticity and metaplasticity in motivational and reward-related learning in the hippocampus. I will introduce two representative neuromodulators that are widely studied in reward-related learning (e.g., ghrelin and endocannabinoids) and show how they might contribute to hippocampal neuron activities and Ca(2+)-mediated signaling processes in synaptic plasticity. Additionally, I will discuss functional significance of these two systems and their signaling pathways for its relevance to maladaptive reward learning leading to addiction.

Figure 1

Hippocampal glutamatergic outputs regulate reward responses in the nucleus accumbens (modified from [1]). NAc: nucleus accumbens, PFC: prefrontal cortex, vSub: ventral subiculum, VTA: ventral tegmental area (modified from [1]).

Figure 2

Colocalization of dopamine receptors and glutamate receptors leads to activation of intracellular transduction mechanisms, induction of regulatory transcription factors, and ultimately long-term changes in cellular plasticity in the hippocampus. AC: adenylyl cyclase, AMPA: α-amino-3-hydroxy-5-methyl-4 isoxazolepropionic acid receptor, CREB: cAMP-response element binding protein, DA:dopamine, DARPP-32: Dopamine, cAMP-regulated phosphoprotein of 32,000 kDa, ERK: extracellular signal-regulated kinase, GLU: glutamate, GluR5:Metabolic glutamate receptor type 5, MAPK: mitogen-activated protein kinase, NMDA: N-methyl d-aspartate receptor, PKA: protein kinase A, VGCC: voltage-gated calcium channel. (Adopted and modified from [13]).

Figure 3

Phosphorylation of NR1 subunit of the NMDA receptor (pNR1) was immunohistochemically detected using an antibody. pNR1 immunoreactivity increased in response to ghrelin (b) when compared with control (a). This effect was blocked by the antagonist of the ghrelin receptor, L-Dys3-GHSR (c). Calibcation: 5 μm. Adopted and modified from Cuellar and Isokawa [24].

Figure 4

Activation of RyR can provide Ca²⁺ to a distant mobilization site of eCBs away from the Ca²⁺entry site.

Figure 5

Endocannabinoids negatively regulate ghrelin-induced enhancement of synaptic receptor functions by inhibiting the phosphorylation of NR1. CB1R (type 1 cannabinoid receptor), GHSR1a (type 1a ghrelin receptor, aka growth hormone secretagogue receptor), PKA (protein kinase A), RYR (ryanodine receptor), ER (endoplasmic reticulum), L-VGCC (L-type voltage-gated calcium channel), 2-AG (2-arachidonoyl glycerol).