Rett syndrome (RTT) is a neurodevelopmental disorder caused by mutations in the X-linked methyl-CpG-binding-protein-2 (MECP2) gene, which encodes the transcriptional modulator MeCP2. Cognitive and attentional impairments are hallmarks of RTT (Berger-Sweeney, 2011; Rose et al., 2013, 2016), which is characterised by apparently normal initial development and subsequent social and motor deficits, distorted breathing pattern, and severe cognitive regression (Chahrour and Zoghbi, 2007). The central dopaminergic system has been implicated in attention (Robinson and Gradinaru, 2018) and cognitive control (Cools and D'Esposito, 2011). Therefore, an altered dopaminergic system is likely to be involved in cognitive and attentional impairments in patients with RTT and animal models. Indeed, in mouse models for RTT, dysregulation of dopamine neurotransmission in the mesolimbic (Fukuhara et al., 2019) and nigrostriatal (Liao, 2019) pathways associated with reward and motor function, respectively, has been reported. However, the function of dopamine neurotransmission in the mesocortical pathway, which is associated with attention and cognitive function, is not fully investigated despite cognitive impairment in RTT.

Ghrelin, an orexigenic peptide hormone predominantly secreted from the stomach (Kojima and Kangawa, 2002), plays a key role in the regulation of neural plasticity, attention, and cognition (Ghosh-Swaby et al., 2022). For instance, the improvement of cognitive function by ghrelin or ghrelin receptor (growth hormone secretagogue receptor; GHSR) agonists has been reported in various animal models with cognitive deficits, including Alzheimer's disease (Goshadrou et al., 2018; Jeon et al., 2019; Kunath et al., 2015; Santos et al., 2017), Parkinson's disease (Morgan et al., 2018), depression (Li et al., 2021), traumatic brain injury (Kenny et al., 2013), and scopolamine-induced deficit (Atcha et al., 2009). Furthermore, the role of ghrelin in attention-like behaviours has been demonstrated in ghrelin-deficient zebrafish (Shi et al., 2021). However, the beneficial effect of ghrelin on cognitive and attentional impairments in developmental disorders, such as RTT is unknown. Ghrelin and GHSR agonists affect dopamine neurotransmission in various brain regions, including mesocorticolimbic pathways (Kawahara et al., 2009; Pierre et al., 2020). Moreover, ghrelin amplifies dopamine D1 receptor signalling in neurons that co-express D1 receptors and GHSRs, which are found in the cortex and ventral tegmental area (VTA) (Jiang et al., 2006). As optimal activation of dopamine D1 receptor signalling in the PFC is required for cognitive and attentional performance (Arnsten, 1997; Cools and D'Esposito, 2011; Wulaer et al., 2021), we hypothesized that the D1 receptor-mediated dopaminergic neurotransmission would be altered in Mecp2 KO mice, a mouse model of RTT, and that ghrelin could optimise dopamine neurotransmission in the PFC, thereby improving dopamine-related behaviours, including cognition and attention.

To test this hypothesis, we investigated the dopamine neurotransmission in the PFC using in vivo microdialysis and found that the dopamine responses to external stimuli were attenuated due to the alterations of D1 receptor signalling in Mecp2 KO mice. Ghrelin restored the attenuated dopamine neurotransmission by adjusting the altered D1 receptor function in the PFC of Mecp2 KO mice. Behavioural analyses revealed that ghrelin enhanced the exploratory activity toward objects, but did not improve cognitive function in Mecp2 KO mice. This behavioural improvement is likely mediated through the normalisation of dopamine neurotransmission.