title: A BDNF loop-domain mimetic acutely reverses spontaneous apneas and respiratory abnormalities during behavioral arousal in a mouse model of Rett syndrome.
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.
authors.affiliation: Department of Neurosciences, Case Western Reserve University School of Medicine, 10900 Euclid Avenue, Cleveland, OH 44106, USA.
authors.forename: Miriam
authors.initials: M
authors.lastname: Kron
authors.affiliation: Department of Neurosciences, Case Western Reserve University School of Medicine, 10900 Euclid Avenue, Cleveland, OH 44106, USA.
authors.forename: Min
authors.initials: M
authors.lastname: Lang
authors.affiliation: Department of Neurosciences, Case Western Reserve University School of Medicine, 10900 Euclid Avenue, Cleveland, OH 44106, USA.
authors.forename: Ian T
authors.initials: IT
authors.lastname: Adams
authors.affiliation: Department of Neurosciences, Case Western Reserve University School of Medicine, 10900 Euclid Avenue, Cleveland, OH 44106, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Sceniak
authors.affiliation: Department of Neurology and Neurological Sciences, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, CA 94305, USA.
authors.forename: Frank
authors.initials: F
authors.lastname: Longo
authors.affiliation: Department of Neurosciences, Case Western Reserve University School of Medicine, 10900 Euclid Avenue, Cleveland, OH 44106, USA david.katz@case.edu.
authors.forename: David M
authors.initials: DM
authors.lastname: Katz
mesh_terms: D000818:Animals; D001049:Apnea / Q000517:prevention & control*; D019208:Brain-Derived Neurotrophic Factor / Q000737:chemistry / Q000502:physiology*; D002227:Carbazoles / Q000494:pharmacology; D004195:Disease Models, Animal; D006801:Humans; D026121:Indole Alkaloids / Q000494:pharmacology; D051783:Methyl-CpG-Binding Protein 2 / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D012119:Respiration; D015518:Rett Syndrome / Q000503:physiopathology*
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D002227:Carbazoles; D026121:Indole Alkaloids; C497393:Mecp2 protein, mouse; D051783:Methyl-CpG-Binding Protein 2; D047428:Protein Kinase Inhibitors; C049985:staurosporine aglycone
keywords: Arousal; Brain-derived neurotrophic factor (BDNF); Brainstem; Mecp2; Respiration