Ghrelin restores D1 receptor-mediated dopamine neurotransmission and enhances attentive behaviour in Mecp2 KO mice

Rett syndrome is an X-linked neurodevelopmental disorder characterised by cognitive, attentional, and communicative impairments along with sensory and motor deficits. Optimal activation of dopamine D1 receptor signalling in the prefrontal cortex (PFC) is essential for cognition and object-based attention. Ghrelin has been observed to modulate dopaminergic neurotransmission and improve cognitive function and attention impairments in various animal models. Herein, we investigated the effects of ghrelin on D1 receptor-mediated dopaminergic neurotransmission in the PFC of male Mecp2 knockout (KO) mice, a mouse model of Rett syndrome, using in vivo microdialysis. External stimuli, such as saline injection and novelty induced increases in the 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 dopaminergic responses to external stimuli were attenuated, and the dopamine reuptake system was upregulated. Pharmacological analyses revealed that the ability of D1 receptor signalling to inhibit dopamine release would be upregulated and/or its ability to stimulate dopamine release would be downregulated in Mecp2 KO mice. Ghrelin injection (8.6 μg/mouse, s.c.) restored dopaminergic responses to external stimuli by adjusting the altered function of D1 receptor signalling. While ghrelin injection failed to improve the impaired object recognition ability in Mecp2 KO mice, it enhanced attention and exploratory activity toward objects. These findings in Mecp2 KO mice suggest that ghrelin may enhance D1 receptor-mediated dopaminergic neurotransmission and exert beneficial effects on dopamine-related behaviour, such as attention and investigatory motivation towards objects, in Rett syndrome.