Madm/NRBP1 mediates synaptic maintenance and neurodegeneration-induced presynaptic homeostatic potentiation

The precise regulation of synaptic connectivity and function is essential to maintain neuronal circuits. Here, we show that the Drosophila pseudo-kinase Madm/NRBP1 (Mlf-1-adapter-molecule/nuclear-receptor-binding protein 1) is required presynaptically to maintain synaptic stability and to coordinate synaptic growth and function. Presynaptic Madm mediates these functions by controlling cap-dependent translation via the target of rapamycin (TOR) effector 4E-BP/Thor (eukaryotic initiation factor 4E binding protein/Thor). Strikingly, at degenerating neuromuscular synapses, postsynaptic Madm induces a compensatory, transsynaptic signal that utilizes the presynaptic homeostatic potentiation (PHP) machinery to offset synaptic release deficits and to delay synaptic degeneration. Madm is not required for canonical PHP but induces a neurodegeneration-specific form of PHP and acts via the regulation of the cap-dependent translation regulators 4E-BP/Thor and S6-kinase. Consistently, postsynaptic induction of canonical PHP or TOR activation can compensate for postsynaptic Madm to alleviate functional and structural synaptic defects. Our results provide insights into the molecular mechanisms underlying neurodegeneration-induced PHP with potential neurotherapeutic applications.