Longitudinal behavioral profiling reveals early-onset and persistent motor dysfunction in a VAChT-KD model for congenital myasthenic syndrome.

The vesicular acetylcholine transporter knockdown (VAChT-KD) mouse is a genetic model of congenital myasthenic syndrome (CMS) characterized by impaired cholinergic transmission at the neuromuscular junction, resulting in presynaptic neuromuscular dysfunction. Here, we performed a longitudinal behavioral analysis to determine the onset and progression of motor deficits across development and adulthood, including potential sex-dependent effects. VAChT-KD mice exhibited early and persistent motor impairments. Neonatal animals showed reduced strength, impaired coordination, and delayed motor development compared to controls, and these deficits persisted into adulthood. Motor performance was consistently impaired in tests of global strength, while other behavioral measures revealed age- and sex-dependent differences. Notably, repeated exposure to motor tasks improved performance in mutant mice, indicating a learning component that partially compensates for underlying deficits. Across behavioral paradigms, genotype and age emerged as the primary determinants of motor performance. Importantly, the identification of early disease onset and measurable functional deficits across development highlights a critical window for therapeutic intervention. These findings support the use of VAChT-KD mice as a translational platform for testing early-stage therapies and underscore the importance of considering behavioral adaptation when designing preclinical studies for neuromuscular disorders.