Abstract
Reduced levels of brain-derived neurotrophic factor (BDNF) are thought to contribute to the pathophysiology of Rett syndrome (RTT), a severe neurodevelopmental disorder caused by loss-of-function mutations in the gene encoding methyl-CpG-binding protein 2 (MeCP2). In Mecp2 mutant mice, BDNF deficits have been associated with breathing abnormalities, a core feature of RTT, as well as with synaptic hyperexcitability within the brainstem respiratory network. Application of BDNF can reverse hyperexcitability in acute brainstem slices from Mecp2-null mice, suggesting that therapies targeting BDNF or its receptor, TrkB, could be effective at acute reversal of respiratory abnormalities in RTT. Therefore, we examined the ability of LM22A-4, a small-molecule BDNF loop-domain mimetic and TrkB partial agonist, to modulate synaptic excitability within respiratory cell groups in the brainstem nucleus tractus solitarius (nTS) and to acutely reverse abnormalities in breathing at rest and during behavioral arousal in Mecp2 mutants. Patch-clamp recordings in Mecp2-null brainstem slices demonstrated that LM22A-4 decreases excitability at primary afferent synapses in the nTS by reducing the amplitude of evoked excitatory postsynaptic currents and the frequency of spontaneous and miniature excitatory postsynaptic currents. In vivo, acute treatment of Mecp2-null and -heterozygous mutants with LM22A-4 completely eliminated spontaneous apneas in resting animals, without sedation. Moreover, we demonstrate that respiratory dysregulation during behavioral arousal, a feature of human RTT, is also reversed in Mecp2 mutants by acute treatment with LM22A-4. Together, these data support the hypothesis that reduced BDNF signaling and respiratory dysfunction in RTT are linked, and establish the proof-of-concept that treatment with a small-molecule structural mimetic of a BDNF loop domain and a TrkB partial agonist can acutely reverse abnormal breathing at rest and in response to behavioral arousal in symptomatic RTT mice.
Highlights
Complex respiratory disturbances, including atypical respiratory pauses and apneas, are a prominent feature of Rett syndrome (RTT), severely impacting health and quality of life (Katz et al, 2009; Ramirez et al, 2013)
LM22A-4 reduces synaptic excitability in the lateral, ventrolateral and interstitial subnuclei of Mecp2-null mice We previously showed that Mecp2-null mice exhibit synaptic hyperexcitability within respiratory cell groups in the nucleus of the solitary tract (nTS), including in the lateral, ventrolateral and interstitial subnuclei
The present results demonstrate the reversibility of synaptic and behavioral phenotypes associated with abnormal breathing in symptomatic Mecp2 mutant mice, a model of RTT
Summary
Complex respiratory disturbances, including atypical respiratory pauses and apneas, are a prominent feature of Rett syndrome (RTT), severely impacting health and quality of life (Katz et al, 2009; Ramirez et al, 2013). Hyperexcitability within lateral subnuclei of the Mecp mutant nTS, where pulmonary stretch receptors form the first synapse in the Hering-Breuer reflex (HBR) pathway (Kubin et al, 2006), would be expected to decrease the activation threshold for the inspiratory off-switch and thereby promote the generation of apneas in RTT. These data suggest that therapeutic strategies aimed at restoring normal sensory gating in nTS by reducing synaptic hyperexcitability might ameliorate abnormal breathing in Mecp mutant mice
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