The Calcium-Activated Chloride Channel TMEM16F Acts at C-Bouton to Modulate Motor Resistance and Contributes to ALS Pathogenesis

Abstract

Neuronal Ca2+ entry elicited by electrical activity contributes to information coding via activation of K+ and Cl- channels. While Ca2+-dependent K+ channels have been extensively studied, the molecular identity and role of Ca2+-activated Cl- channels (CaCC) remains however unclear. Here, we show the CaCC encoded by Tmem16f is specifically expressed as clusters in α-motoneurons of the ventral spinal cord facing the pre-synaptic cholinergic C-boutons. Tmem16f-deficient mice display decreased motor performance under high-task exercise attributable to an increase of recruitment threshold of fast α-motoneurons. Remarkably, the deletion of TMEM16F in a mouse model of the amyotrophic lateral sclerosis (ALS) significantly reduces activity-dependent early stress marker expression, muscle denervation, preserves muscular force and delays disease progression. Thus, as a novel component of C-bouton, TMEM16F controls motoneuron excitability and impacts motor resistance as well as motor deterioration in ALS.