Agonist stimulated 5-HT7R recovers gene expression profile in cortical neurons of a Rett syndrome mouse model

Rett Syndrome (RTT, MIM #312750) is a progressive X-linked neurodevelopmental disorder affecting mainly girls during early childhood. MECP2 gene mutations are the main cause for RTT1, but how they lead to the neuropathological signs of RTT is unknown and no cure is available. We show that alterations of both neuronal branching and gene expression can be observed in the Mecp2-KO mice at early embryonic developmental stage (E15dpc- cortical neurons). The in vitro stimulation of the serotonin receptor 7 (5-HT7R) with a brain penetrant selective agonist (LP-2112,3) normalizes the morphological phenotype due to MeCP2 loss. From RNA-sequencing analysis applied to neurons dissected from wt and null mice, we determinate there are two sets of genes, one affected only by Mecp2 deficiency and the other responding to LP-211. Among the agonist-responding genes we distinguish: i) rescued genes (deregulated in the Mecp2 null neurons and rescuing a level of physiological expression as consequence of treatment); ii) newly recruited genes (normally expressed in null neurons and differentially expressed upon treatment). Using in-house built software Transcriptator we annotate the functional and gene ontological terms associated with these sets of transcripts, finding both specific and common annotation terms. We find agonist-responding genes that may account for shaping neuronal morphology, as they are involved in regulation of transcription in neurogenesis, cytoskeleton dynamics and receptor-mediated pathways. Finally, we investigate the possible involvement of transcription factors such as SRF (serum responding factor)4 as nuclear downstream effectors of 5-HT7R stimulation and to gain insights on the molecular mechanism acting on LP-211 responding genes.