AbstractPresynaptic homeostatic plasticity (PHP) stabilizes synaptic transmission by counteracting impaired neurotransmitter receptor function through increased presynaptic release. PHP is thought to be triggered by impaired receptor function, and to involve a stereotypic signaling pathway. However, here we demonstrate that different receptor perturbations that similarly impair synaptic activity result in vastly different responses at the Drosophila neuromuscular junction. While competitive receptor inhibition is not compensated by PHP, receptor pore block and allosteric inhibition induce compensatory PHP. Intriguingly, PHP triggered by receptor pore block and allosteric inhibition involve distinct presynaptic adaptations, including differential modulation of the active-zone scaffold Bruchpilot and short-term plasticity. Moreover, while PHP upon allosteric receptor inhibition does not require molecules underlying pore-block induced PHP (RIM and dysbindin), it is promoted by presynaptic Protein Kinase D. Thus, synapses not only respond differentially to similar activity impairments, but achieve homeostatic compensation via distinct mechanisms, highlighting the diversity of homeostatic signaling.
GPI-1046 Increases Presenilin-1 Expression and Restores NMDA Channel Activity
