PROJECT SUMMARY Stable functionality in the nervous system is maintained despite the challenges associated with development, growth, experience, aging, and disease. This remarkable stability is controlled by potent and adaptive homeostatic signaling systems that sustain robust and reliable information transfer across synapses. Synapses are therefore critical substrates to achieve and maintain the homeostatic control of neural activity. Indeed, homeostatic synaptic plasticity is fundamental form of plasticity endowed at synapses in the central and peripheral nervous systems of invertebrates, rodents, and humans. Defects in homeostatic signaling contribute to the etiology of a variety of neurological diseases including epilepsy, Fragile X Syndrome, and neurodegeneration. However, the molecular mechanisms that induce and sustain homeostatic plasticity remain enigmatic. To understand synaptic dysfunction during disease states, we must first decipher the intercellular dialogue that controls homeostatic signaling. Our long-term goals are to define the mechanisms that achieve and maintain the homeostatic control of synaptic function in health and disease. Towards this end, we have pioneered forward genetic screens using electrophysiology that have discovered new genes and revealed fundamental mechanisms mediating homeostatic signaling at the Drosophila neuromuscular junction. At this model glutamatergic synapse, acute pharmacological inhibition or chronic genetic elimination of postsynaptic glutamate receptors (GluRs) triggers a retrograde signaling system in the postsynaptic compartment that precisely increases presynaptic neurotransmitter release to maintain stable synaptic strength. This process is referred to as Presynaptic Homeostatic Potentiation (PHP). Work from the Dickman lab and others have uncovered many presynaptic genes that converge on two key mechanisms that serve to increase neurotransmitter release and enable the expression of PHP. In addition, candidate retrograde signals have also been identified. In contrast to the emerging framework from which we now understand how enhanced presynaptic neurotransmitter release is controlled following PHP expression, almost nothing is known about the signaling system in the postsynaptic compartment that senses diminished GluR function and transforms this into tunable information transmitted to specific presynaptic compartments. Therefore, illuminating the nature of the postsynaptic induction mechanisms that initiate and maintain PHP will be the primary goal of this proposal. In this supplement, we propose to investigate the function of two newly identified postsynaptic genes, peflin and ALG2, in retrograde homeostatic signaling.