Motoneuron‐specific loss of VAChT mimics neuromuscular defects seen in congenital myasthenic syndrome

Motoneurons (MNs) control muscle activity by releasing the neurotransmitter acetylcholine (ACh) at level of neuromuscular junctions. ACh is packaged into synaptic vesicles vesicular transporter (VAChT), and disruptions in its release can impair contraction, as seen congenital myasthenic syndromes (CMS). Recently, VAChT gene mutations were identified humans displaying varying degrees myasthenia. Moreover, mice with a global deficiency expression display several characteristics CMS. Despite these findings, little known about how long-term decrease vivo affects MNs structure function. Using Cre-loxP technology, we generated mouse model where deleted select groups (mnVAChT-KD). Molecular analysis revealed that deletion was specific to affected approximately 50% population brainstem spinal cord, alpha-MNs primarily targeted (70% cord). Within each animal, cell body area VAChT-deleted significantly smaller compared preserved. Likewise, muscles innervated showed atrophy while VAChT-containing neurons appeared normal. In addition, mnVAChT KD had decreased strength, hypoactive, leaner exhibited kyphosis. This dysfunction evident 2 months age became progressively worse 6 months. Treatment mutants cholinesterase inhibitor able improve some motor deficits. As observations mimic what CMS, this new line could be valuable for assessing efficacy potential CMS drugs.