Role of Dopamine D3 receptor in the regulation of memory related genes

Abstract

Dopamine is postulated to be a key neurotransmitter that mediates human memory via signaling in the striatum, hippocampus and prefrontal cortex. The effects of dopaminergic system crucially depend on the different subtype of dopamine receptors involved and the brain regions in which they are activated. D3 receptors (D3R) are more selectively expressed in the limbic regions, which are associated with cognitive and emotional functions. However, few studies have focused on the effect of D3R deficiency on learning and memory processes and underlying molecular events. To elucidate the potential role of D3R in associative learning and underlying molecular events, we used D3R knockout (D3-/-) mice in order to explore the intracellular signaling pathways using Passive avoidance (PA) tasks. In the first study we evaluated the expression levels of APP and NF1, two genes implicated in cognitive function, in wild-type (WT) and D3-/- mice subjected to the single trial step-through PA paradigm. Results showed that acquisition of behavioral task leads to increased expression levels of D3Rs and NF1, but not of APP in hippocampus of WT mice, suggesting that hippocampal D3Rs might be relevant to NF1 transcriptional regulation in the hippocampus. In the second study we tested the involvement of signaling molecules MAPKs, Akt and CREB to assess whether their phosphorylation levels were affected by PA in wild-type (WT) and D3-/- mice hippocampi. Increased phosphorylation levels of CREB and ERK were detected in D3-/- mice performing PA task, while Akt activation was observed in D3-/- mice, but not in response to PA. Results suggest that D3R inactivation might improve cognitive performance in mice through the induction of hippocampal CREB activity, preferentially via ERK signaling. The aim of third work was determine whether D3R deletion influences baseline tPA expression/activity in prefrontal cortex and hippocampus, and subsequently elucidate the potential underlying mechanisms mediated by D3R to regulate CREB activity in tPA. Results revealed that in prefrontal cortex and hippocampus of D3-/- mice, tPA, mBDNF and the expression ratio of plasmin/plasminogeno both mRNA and protein expression levels were significantly increased as compared to the WT mice. Datas showed increased Akt, DARPP-32 and GSK-3B phospshorylation in D3-/- mice, suggesting that this pathaways is involved in raised tPA expression in D3-/- mice.