The tyrosine phosphatase receptor Lar regulates post-synaptic boutons morphology, glutamate receptor levels, and cytoplasmic Ca²⁺ clearing

The neuromuscular junction (NMJ) is the contact site between motor neurons and muscle fibers, and its size and morphology are tightly linked to the extent, and duration of motor neuron activity. Muscles respond to signals secreted from the motor neuron ends by developing corresponding post-synaptic sites in which glutamate receptors, in the case of Drosophila larvae, accumulate to enable efficient transmission of the motor neuron signal. Both the number of synaptic boutons and the extent of their branching are highly stereotyped in Drosophila larval 3^rd instar stage.

Whereas Leukocyte-antigen-related-like receptor (Lar) is essential for motor axon navigation at the axon side, we discovered a specific function for Lar at the post-synaptic site. First, we show that Lar localizes at the post-synaptic sites of 3^rd instar larvae, by CRISPR-mediated insertion of HA tag at the C-terminal end of Lar. Then, a muscle-specific knockdown of Lar was performed and led to severe impairment in larval locomotion and growth. Further analysis indicated a phenotype of disorganized post-synaptic boutons, with aberrant morphology, which also correlated with reduced levels of Glutamate receptors (GluR), and loose sarcoplasmic reticulum (SR) at the post-synaptic site. Furthermore, live imaging of larvae expressing fluorescent Ca²⁺ marker (GCaMP) indicated that Ca²⁺ clearing from the muscle cytoplasm was attenuated in Lar knocked-down muscles, which also correlated with increased autophagy.

Taken together these results imply a specific function for Lar at the post-synaptic site, which differs from that at the pre-synaptic site, and is required to regulate the tight association between the synaptic membrane and the sarcoplasmic reticulum.