Ghrelin ameliorates cognitive deficits and restores dopamine responses to external stimuli in the PFC via D1 receptor signaling in Mecp2 KO mice, a mouse model for Rett syndrome

Rett syndrome is an X-linked neurodevelopmental disorder characterized by cognitive impairments along with sensory and motor deficits. Ghrelin is known to improve cognitive function in various animal models with cognitive deficits. Optimum activation of dopamine D1 receptor signaling in the prefrontal cortex (PFC) plays a critical role in cognitive performance. In this study, we investigated the effects of ghrelin on cognitive function and D1 receptor-mediated dopamine neurotransmission in the PFC of Mecp2 knockout (KO) mice, a mouse model for Rett syndrome. In the modified novel object recognition test, cognitive function was impaired in Mecp2 KO mice, and ghrelin injection (8.6 µg/mouse, s.c.) improved the cognition of objects and investigatory behaviors. In in vivo microdialysis studies, external stimuli such as saline injection and novelty induced increases in dopamine levels in the PFC of wild-type mice, and the dopamine release was bidirectionally regulated by D1 receptors. In the PFC of Mecp2 KO mice, the dopamine responses to external stimuli were attenuated and the dopamine reuptake system was upregulated. Pharmacological analyses revealed that the ability of D1 receptor signaling to inhibit dopamine release would be upregulated and/or its ability to stimulate dopamine release would be downregulated in Mecp2 KO mice. Ghrelin injection restored dopamine responses to external stimuli by adjusting the altered function of D1 receptor signaling. These results suggest that the ability of ghrelin to restore dopamine neurotransmission via D1 receptor-mediated mechanisms likely contributes to its therapeutic effects on cognitive deficits in Mecp2 KO mice.