{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T13:27:18Z","timestamp":1791293238178,"version":"4.1.0"},"reference-count":50,"publisher":"The Company of Biologists","issue":"9","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2014,9,1]]},"abstract":"<jats:p>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.<\/jats:p>","DOI":"10.1242\/dmm.016030","type":"journal-article","created":{"date-parts":[[2014,8,21]],"date-time":"2014-08-21T13:21:42Z","timestamp":1408627302000},"page":"1047-1055","source":"Crossref","is-referenced-by-count":59,"title":["A BDNF loop-domain mimetic acutely reverses spontaneous apneas and respiratory abnormalities during behavioral arousal in a mouse model of Rett syndrome"],"prefix":"10.1242","volume":"7","author":[{"given":"Miriam","family":"Kron","sequence":"first","affiliation":[{"name":"Department of Neurosciences, Case Western Reserve University School of Medicine, 10900 Euclid Avenue, Cleveland, OH 44106, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min","family":"Lang","sequence":"additional","affiliation":[{"name":"Department of Neurosciences, Case Western Reserve University School of Medicine, 10900 Euclid Avenue, Cleveland, OH 44106, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ian T.","family":"Adams","sequence":"additional","affiliation":[{"name":"Department of Neurosciences, Case Western Reserve University School of Medicine, 10900 Euclid Avenue, Cleveland, OH 44106, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Sceniak","sequence":"additional","affiliation":[{"name":"Department of Neurosciences, Case Western Reserve University School of Medicine, 10900 Euclid Avenue, Cleveland, OH 44106, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frank","family":"Longo","sequence":"additional","affiliation":[{"name":"Department of Neurology and Neurological Sciences, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, CA 94305, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David M.","family":"Katz","sequence":"additional","affiliation":[{"name":"Department of Neurosciences, Case Western Reserve University School of Medicine, 10900 Euclid Avenue, Cleveland, OH 44106, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"237","reference":[{"key":"2021042501181048100_b1-0071047","doi-asserted-by":"crossref","first-page":"18208","DOI":"10.1073\/pnas.1012104107","article-title":"Correction of respiratory disorders in a mouse model of Rett syndrome","volume":"107","author":"Abdala","year":"2010","journal-title":"Proc. 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Neurosci."},{"key":"2021042501181048100_b38-0071047","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1016\/j.neulet.2008.09.045","article-title":"Tyrosine hydroxylase deficit in the chemoafferent and the sympathoadrenergic pathways of the Mecp2 deficient mouse","volume":"447","author":"Roux","year":"2008","journal-title":"Neurosci. Lett."},{"key":"2021042501181048100_b39-0071047","doi-asserted-by":"crossref","first-page":"4527","DOI":"10.1523\/JNEUROSCI.17-12-04527.1997","article-title":"Brain-derived neurotrophic factor mediates the activity-dependent regulation of inhibition in neocortical cultures","volume":"17","author":"Rutherford","year":"1997","journal-title":"J. Neurosci."},{"key":"2021042501181048100_b40-0071047","doi-asserted-by":"crossref","first-page":"1803","DOI":"10.1523\/JNEUROSCI.0865-11.2012","article-title":"A TrkB small molecule partial agonist rescues TrkB phosphorylation deficits and improves respiratory function in a mouse model of Rett syndrome","volume":"32","author":"Schmid","year":"2012","journal-title":"J. Neurosci."},{"key":"2021042501181048100_b41-0071047","doi-asserted-by":"crossref","first-page":"18712","DOI":"10.1523\/JNEUROSCI.1310-13.2013","article-title":"A small molecule TrkB ligand reduces motor impairment and neuropathology in R6\/2 and BACHD mouse models of Huntington\u2019s disease","volume":"33","author":"Simmons","year":"2013","journal-title":"J. Neurosci."},{"key":"2021042501181048100_b42-0071047","doi-asserted-by":"crossref","first-page":"863","DOI":"10.1113\/jphysiol.2006.119966","article-title":"Breathing dysfunctions associated with impaired control of postinspiratory activity in Mecp2-\/y knockout mice","volume":"579","author":"Stettner","year":"2007","journal-title":"J. Physiol."},{"key":"2021042501181048100_b43-0071047","doi-asserted-by":"crossref","first-page":"7685","DOI":"10.1523\/JNEUROSCI.23-20-07685.2003","article-title":"Expression of functional tyrosine kinase B receptors by rhythmically active respiratory neurons in the pre-B\u00f6tzinger complex of neonatal mice","volume":"23","author":"Thoby-Brisson","year":"2003","journal-title":"J. Neurosci."},{"key":"2021042501181048100_b44-0071047","doi-asserted-by":"crossref","first-page":"e87923","DOI":"10.1371\/journal.pone.0087923","article-title":"A monoclonal antibody TrkB receptor agonist as a potential therapeutic for Huntington\u2019s disease","volume":"9","author":"Todd","year":"2014","journal-title":"PLoS ONE"},{"key":"2021042501181048100_b45-0071047","doi-asserted-by":"crossref","first-page":"11521","DOI":"10.1523\/JNEUROSCI.4373-05.2005","article-title":"Mecp2 deficiency disrupts norepinephrine and respiratory systems in mice","volume":"25","author":"Viemari","year":"2005","journal-title":"J. Neurosci."},{"key":"2021042501181048100_b46-0071047","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1016\/j.resp.2011.02.002","article-title":"The benzodiazepine Midazolam mitigates the breathing defects of Mecp2-deficient mice","volume":"177","author":"Voituron","year":"2011","journal-title":"Respir. Physiol. 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