Chemogenetic inhibition of TrkB signalling reduces phrenic motor neuron survival and size

• Published in: Molecular and cellular neuroscience 2023-06, Vol.125, p.103847-103847, Article 103847
• Main Authors: Fogarty, Matthew J., Dasgupta, Debanjali, Khurram, Obaid U., Sieck, Gary C.
• Format: Article
• Language: English
• Subjects: Animals; Biological Transport; Brain-Derived Neurotrophic Factor - metabolism; Female; Male; Motor Neurons - metabolism; Neural plasticity; Neurotrophins; Phrenic motor neurons; Rats; Rats, Sprague-Dawley; Receptor, trkB - metabolism; Retrograde transport; Signal Transduction; Spinal Cord - metabolism
• ISSN: 1044-7431; 1095-9327
• DOI: 10.1016/j.mcn.2023.103847

Brain derived neurotrophic factor (BDNF) signalling through its high-affinity tropomyosin receptor kinase B (TrkB) is known to have potent effects on motor neuron survival and morphology during development and in neurodegenerative diseases. Here, we employed a novel 1NMPP1 sensitive TrkBF616 rat model to evaluate the effect of 14 days inhibition of TrkB signalling on phrenic motor neurons (PhMNs). Adult female and male TrkBF616 rats were divided into 1NMPP1 or vehicle treated groups. Three days prior to treatment, PhMNs in both groups were initially labeled via intrapleural injection of Alexa-Fluor-647 cholera toxin B (CTB). After 11 days of treatment, retrograde axonal uptake/transport was assessed by secondary labeling of PhMNs by intrapleural injection of Alexa-Fluor-488 CTB. After 14 days of treatment, the spinal cord was excised 100 μm thick spinal sections containing PhMNs were imaged using two-channel confocal microscopy. TrkB inhibition reduced the total number of PhMNs by ∼16 %, reduced the mean PhMN somal surface areas by ∼25 %, impaired CTB uptake 2.5-fold and reduced the estimated PhMN dendritic surface area by ∼38 %. We conclude that inhibition of TrkB signalling alone in adult TrkBF616 rats is sufficient to lead to PhMN loss, morphological degeneration and deficits in retrograde axonal uptake/transport. •In retrogradely labeled phrenic motor neurons (PhMNs), chemogenetic BDNF/TrkB inhibition in the novel TrkBF616 rat leads to PhMN death and reduced axonal transport in otherwise healthy adults.•To our knowledge this is the first direct report of motor neuron loss due solely to reduced BDNF/TrkB signaling in adult rats. Our findings have implications for scenarios where BDNF/TrkB signaling is impaired, such as in ALS and aging.