Abstract
Rett syndrome (RTT) is a rare neurodevelopmental disorder, characterized by severe behavioral and physiological symptoms. Mutations in the methyl CpG binding protein 2 gene (MECP2) cause more than 95% of classic cases, and currently there is no cure for this devastating disorder. Recently we have demonstrated that specific behavioral and brain molecular alterations can be rescued in MeCP2-308 male mice, a RTT mouse model, by pharmacological stimulation of the brain serotonin receptor 7 (5-HT7R). This member of the serotonin receptor family—crucially involved in the regulation of brain structural plasticity and cognitive processes—can be stimulated by systemic repeated treatment with LP-211, a brain-penetrant selective 5-HT7R agonist. The present study extends previous findings by demonstrating that the LP-211 treatment (0.25 mg/kg, once per day for 7 days) rescues RTT-related phenotypic alterations, motor coordination (Dowel test), spatial reference memory (Barnes maze test) and synaptic plasticity (hippocampal long-term-potentiation) in MeCP2-308 heterozygous female mice, the genetic and hormonal milieu that resembles that of RTT patients. LP-211 also restores the activation of the ribosomal protein (rp) S6, the downstream target of mTOR and S6 kinase, in the hippocampus of RTT female mice. Notably, the beneficial effects on neurobehavioral and molecular parameters of a seven-day long treatment with LP-211 were evident up to 2 months after the last injection, thus suggesting long-lasting effects on RTT-related impairments. Taken together with our previous study, these results provide compelling preclinical evidence of the potential therapeutic value for RTT of a pharmacological approach targeting the brain 5-HT7R.
Highlights
The serotonin receptor 7 (5-HT7R), coded by Htr7 gene, is among the most recently discovered serotonin receptors (Barnes and Sharp, 1999)
Consistent with previous evidence pointing to Rho GTPases as therapeutic targets for Rett syndrome (RTT) (De Filippis et al, 2012) and with previous studies suggesting that serotonergic neurotransmission is deeply affected both in RTT patients and animal models (Isoda et al, 2010; Santos et al, 2010; Moroto et al, 2013), we demonstrated that a seven-day-long treatment with LP-211 reverses anxiety-related profiles in a Light/Dark test, motor abilities in a Dowel test, the exploratory behavior in the Marble Burying test, as well as short-term working memory in the Y maze task in methyl-CpG-binding protein 2 (MeCP2)-308 hemizygous male mice (Ricceri et al, 2013)
To increase the translational value of the study, we focused on MeCP2-308 heterozygous (Het) female mice, given that their genetic and hormonal milieu more closely resembles that of RTT patients (Katz et al, 2012)
Summary
The serotonin receptor 7 (5-HT7R), coded by Htr gene, is among the most recently discovered serotonin receptors (Barnes and Sharp, 1999). An increasing number of studies demonstrates a role for the 5-HT7R on cognitive processes ( on hippocampal-dependent learning and memory) and in the regulation of structural plasticity in adolescent and mature brain circuits (Gasbarri and Pompili, 2014; Meneses, 2014; Volpicelli et al, 2014; Canese et al, 2015) Consistent with these observations, the 5-HT7R activation stimulates signaling cascades known to play a prominent role in synaptic plasticity and cognition, with the more prominent downstream effectors being represented by the extracellularsignal regulated kinases (ERKs), the cyclic AMP protein kinase (PKA) and the Cyclin-dependent kinase 5 (Cdk5; Guseva et al, 2014; Volpicelli et al, 2014)
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