Structural abnormalities at neuromuscular synapses lacking multiple syntrophin isoforms

The syntrophins are modular adapter proteins that function by recruiting signaling molecules to the cytoskeleton via their direct association with proteins of the dystrophin protein family. We investigated the physiological function of β2-syntrophin by generating a line of mice lacking this syntrophin isoform. The β2-syntrophin null mice show no overt phenotype, or muscular dystrophy, and form structurally normal neuromuscular junctions (NMJs). To determine whether physiological consequences caused by the lack of β2-syntrophin were masked by compensation from the α-syntrophin isoform, we crossed these mice with our previously described α-syntrophin null mice to produce mice lacking both isoforms. The α/β2-syntrophin null mice have NMJs that are structurally more aberrant than those lacking only á-syntrophin. The NMJs of the α/β2-syntrophin null mice have fewer junctional folds than either parent strain, and the remaining folds are abnormally shaped with few openings to the synaptic space. The levels of acetylcholine receptors are reduced to 23% of wild type in mice lacking both syntrophin isoforms. Furthermore, the α/β2-syntrophin null mice ran significantly shorter distances on voluntary exercise wheels despite having normal neuromuscular junction transmission as determined by microelectrode recording of endplate potentials. We conclude that both α-syntrophin and α/β2-syntrophin play distinct roles in forming and maintaining NMJ structure and that each syntrophin can partially compensate for the loss of the other.