Homeostatic Stabilization of Neural Function in Health and Disease - ABSTRACT Homeostatic plasticity (HP) encompasses a suite of compensatory physiological processes that stabilize neural function. It is widely hypothesized that homeostatic plasticity will be linked to the cause and/or severity of neurodevelopmental disorders including autism and intellectual disability. Yet, there remains limited molecular, mechanistic information to directly connect homeostatic plasticity to neurological and neurodevelopmental disorders. We recently made two significant advances in the field. First, we provide evidence that presynaptic homeostatic plasticity (PHP) is neuroprotective in mouse models of amyotrophic lateral sclerosis (ALS). This has given rise to the concept of homeostatic neuroprotection. Second, we have established that PHP is a potent form of homeostatic plasticity expressed in the adult mouse brain, with a specific focus on hippocampus. As a consequence, we have now established a pipeline using genome-scale forward genetic screens in Drosophila to discover fundamental mechanisms of PHP. These mechanisms are then translated to the mouse neuromuscular junction and adult mouse hippocampal preparations to test conservation of function. If conserved, we determine the intersection of new homeostatic mechanisms with the pathophysiology of mouse models of neuromuscular and central degeneration including ALS and FTD. To date, all of the core molecular mechanisms necessary for PHP, first identified in Drosophila, are conserve in mice, both centrally and peripherally. We will continue to harness this highly effective strategy to identify the first positive genetic modulators of PHP, with a goal of promoting homeostatic plasticity and enhancing neurological resilience to disease. We propose that this will pave a new path toward therapeutic development based on the rational manipulation of homeostatic plasticity.
