グレリンはレット症候群モデルマウスの前頭前野D1受容体シグナルを介してドパミン応答を回復させ認知機能障害を改善する

抄録

Ghrelin improves cognition in various animal models with cognitive deficits. This study investigated the effects of ghrelin on cognitive deficits and modulation of D1 receptor signaling in the PFC, which plays a critical role in cognitive performance, in Mecp2 knockout (KO) mice using in vivo microdialysis.

In the modified novel object recognition (NOR) test, KO mice showed the impairment of cognition. Ghrelin injection (8.6 microgram/mouse, s.c.) improved the cognition of objects and investigatory behaviors in KO mice. In microdialysis studies, saline injection and novelty induced increases in DA in WT mice, and the increase was not observed in KO mice. Thus, KO mice exhibit the low response of DA to external stimuli in the PFC. The results of the infusions of D1 receptor ligands into the PFC indicate that D1 receptor signaling in WT mice is involved in bidirectional regulatory mechanisms of DA release. In KO mice, the ability of D1 receptor signaling to inhibit DA release would be upregulated under tonic and D1 receptor-stimulated conditions. Ghrelin injection, but not saline injection, increased DA levels in the PFC, and the DA levels significantly increased in response to the novelty after ghrelin injection in KO mice. The DA responses to the ghrelin injection and to the novelty after ghrelin injection in KO mice were completely abolished by the infusion of SCH23390.

Ghrelin restores DA responses to external stimuli by adjusting the altered function of D1 receptor signaling, and the action of ghrelin may underlie the mechanism for ameliorating cognitive deficit in Mecp2 KO mice.