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

Julliane V Joviano-Santos, Ornela Kljakic, Matheus P S Magalhães-Gomes, Priscila Aparecida C Valadão, Leonardo R de Oliveira, Marco A M Prado, Vania F Prado, Cristina Guatimosim

The FEBS journal 2021 Sep

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Motoneurons (MNs) control muscle activity by releasing the neurotransmitter acetylcholine (ACh) at the level of neuromuscular junctions. ACh is packaged into synaptic vesicles by the vesicular ACh transporter (VAChT), and disruptions in its release can impair muscle contraction, as seen in congenital myasthenic syndromes (CMS). Recently, VAChT gene mutations were identified in humans displaying varying degrees of myasthenia. Moreover, mice with a global deficiency in VAChT expression display several characteristics of CMS. Despite these findings, little is known about how a long-term decrease in VAChT expression in vivo affects MNs structure and function. Using Cre-loxP technology, we generated a mouse model where VAChT is deleted in select groups of MNs (mnVAChT-KD). Molecular analysis revealed that the VAChT deletion was specific to MNs and affected approximately 50% of its population in the brainstem and spinal cord, with alpha-MNs primarily targeted (70% in spinal cord). Within each animal, the cell body area of VAChT-deleted MNs was significantly smaller compared to MNs with VAChT preserved. Likewise, muscles innervated by VAChT-deleted MNs showed atrophy while muscles innervated by VAChT-containing neurons appeared normal. In addition, mnVAChT KD mice had decreased muscle strength, were hypoactive, leaner and exhibited kyphosis. This neuromuscular dysfunction was evident at 2 months of age and became progressively worse by 6 months. Treatment of mutants with a cholinesterase inhibitor was able to improve some of the motor deficits. As these observations mimic what is seen in CMS, this new line could be valuable for assessing the efficacy of potential CMS drugs. © 2021 Federation of European Biochemical Societies.

Citation

Julliane V Joviano-Santos, Ornela Kljakic, Matheus P S Magalhães-Gomes, Priscila Aparecida C Valadão, Leonardo R de Oliveira, Marco A M Prado, Vania F Prado, Cristina Guatimosim. Motoneuron-specific loss of VAChT mimics neuromuscular defects seen in congenital myasthenic syndrome. The FEBS journal. 2021 Sep;288(18):5331-5349