Neuromuscular recovery from botulism involves multiple forms of compensatory plasticity

Introduction Botulinum neurotoxin (BoNT) causes neuroparalytic disease and death by blocking neuromuscular transmission. There are no specific therapies for clinical botulism the only treatment option is supportive care until function spontaneously recovers, which can take weeks or months after exposure. The highly specialized junction (NMJ) between phrenic motor neurons diaphragm muscle fibers main target of BoNT. Due to difficulty in eliciting respiratory paralysis without a high mortality rate, few studies have characterized neurophysiological mechanisms involved recovery from intoxication. Here, we develop mouse model that involves partial muscles with low rates, allowing longitudinal analysis recovery. Methods results Mice challenged systemic administration 0.7 LD 50 BoNT/A developed physiological signs botulism, such as depression reduced voluntary running activity, persisted an average 8–12 d. Studies isolated hemidiaphragm preparations intoxicated mice revealed profound reductions nerve-elicited, tetanic twitch contraction strengths recovered baseline 21 d Despite apparent functional recovery, parameters remained depressed 28 d, including end plate potential (EPP) amplitude, EPP success quantal content (QC), miniature (mEPP) frequency. However, QC more quickly than mEPP frequency, could explain discrepancy recordings. Hypothesizing differential modulation voltage-gated calcium channels (VGCC) contributed uncoupling pharmacological inhibition were used study contributions different VGCCs function. We found N-type VGCC P/Q-type partially restored but not frequency during paralysis, potentially explaining accelerated evoked release versus spontaneous release. identified additional changes presumably compensate acetylcholine increased depolarization fiber resting membrane size. Discussion In addition identifying multiple forms compensatory plasticity occur response NMJ function, it expected insights into molecular will support new host-targeted treatments diseases.