Abstract
Rett syndrome is a neurological disorder caused by loss of function of methyl-CpG-binding protein 2 (MeCP2). Reduced function of this ubiquitous transcriptional regulator has a devastating effect on the central nervous system. One of the most severe and life-threatening presentations of this syndrome is brainstem dysfunction, which results in autonomic disturbances such as breathing deficits, typified by episodes of breathing cessation intercalated with episodes of hyperventilation or irregular breathing. Defects in numerous neurotransmitter systems have been observed in Rett syndrome both in animal models and patients. Here we dedicate special attention to serotonin due to its role in promoting regular breathing, increasing vagal tone, regulating mood, alleviating Parkinsonian-like symptoms and potential for therapeutic translation. A promising new symptomatic strategy currently focuses on regulation of serotonergic function using highly selective serotonin type 1A (5-HT1A) “biased agonists.” We address this newly emerging therapy for respiratory brainstem dysfunction and challenges for translation with a holistic perspective of Rett syndrome, considering potential mood and motor effects.
Highlights
Rett syndrome (RTT) is a neurological disorder caused by loss of function of methyl-CpG-binding protein 2 (MeCP2)
In addition to CO2 homeostasis, serotonin is thought to promote regular breathing via activation of 5-HT1A receptors in key brainstem sites involved in termination of inspiration (Richter et al, 2003)
Mice with a geneticallyelicited deletion of 5-HT1A receptors (5-HT1A KO mice) exhibit heightened anxiety-like behavior, as do mice with a heterozygote 5-HT1A genotype that express about half of normal levels of 5-HT1A receptor density. This suggests that even partial decreases in 5-HT1A receptor expression can elicit phenotypically-meaningful increases in anxiety levels
Summary
Rett syndrome (RTT) is a neurological disorder caused by loss of function of methyl-CpG-binding protein 2 (MeCP2). Systemic administration of 5-HT1A agonists produced some of the most robust rescue of respiratory phenotype yet observed in multiple mouse models of Rett syndrome (Levitt et al, 2013; Abdala et al, in press).
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