A selective 5-HT_1areceptor agonist improves respiration in a mouse model of Rett syndrome

Abstract

Rett syndrome is a neurological disorder caused by loss of function mutations in the gene that encodes the DNA binding protein methyl-CpG-binding protein 2 (Mecp2). A prominent feature of the syndrome is disturbances in respiration characterized by frequent apnea and an irregular interbreath cycle. 8-Hydroxy-2-dipropylaminotetralin has been shown to positively modulate these disturbances (Abdala AP, Dutschmann M, Bissonnette JM, Paton JF, Proc Natl Acad Sci U S A 107: 18208-18213, 2010), but the mode of action is not understood. Here we show that the selective 5-HT1a biased agonist 3-chloro-4-fluorophenyl-(4-fluoro-4-{[(5-methylpyrimidin-2-ylmethyl)-amino]-methyl}-piperidin-1-yl)-methanone (F15599) decreases apnea and corrects irregularity in both heterozygous Mecp2-deficient female and in Mecp2 null male mice. In whole cell voltage-clamp recordings from dorsal raphe neurons, F15599 potently induced an outward current, which was blocked by barium, reversed at the potassium equilibrium potential, and was antagonized by the 5-HT1a antagonist WAY100135. This is consistent with somatodendritic 5-HT1a receptor-mediated activation of G protein-coupled inwardly rectifying potassium channels (GIRK). In contrast, F15599 did not activate 5-HT1b/d receptors that mediate inhibition of glutamate release from terminals in the nucleus accumbens by a presynaptic mechanism. Thus F15599 activated somatodendritic 5-HT1a autoreceptors, but not axonal 5-HT1b/d receptors. In unanesthetized Mecp2-deficient heterozygous female mice, F15599 reduced apnea in a dose-dependent manner with maximal effect of 74.5 ± 6.9% at 0.1 mg/kg and improved breath irrregularity. Similarly, in Mecp2 null male mice, apnea was reduced by 62 ± 6.6% at 0.25 mg/kg, and breathing became regular. The results indicate respiration is improved with a 5-HT1a agonist that activates GIRK channels without affecting neurotransmitter release.

MECP2 disorders: from the clinic to mice and back

“…KO animals also exhibit decreased GABA levels in some areas of their brains (57,131), and administration of the GABA reuptake inhibitor NO-711 resulted in a four-fold decrease in apnea frequency (132). Serotonin receptor agonists have also been successful in ameliorating the breathing abnormalities of KO animals (132,133).…”

Optogenetic Approaches to Restoring Vision

“…Banghart et al (2004) demonstrated the first optogenetic pharmacological photoswitches, SPARK, which is attached to an engineered K + channel. Since then, the same strategy has been extended to target the photoswitches to other K + channels (Fortin et al 2011, Sandoz et al 2012, ionotropic and metabotropic glutamate receptors (Levitt et al 2013, Volgraf et al 2007, and nicotinic acetylcholine receptors .…”

Breathing abnormalities in a female mouse model of Rett syndrome

“…Apparently, the age does not correlate well with the early onset of RTT in humans. In another study, breathing abnormalities were observed in Mecp2 ?/-mice 6-17 months, which were reduced by the selective 5HT-1a agonist, F15599 [14].…”