The synaptic active zone as a signaling hub for sleep homeostasis and resilience

Resilience designates the ability of the brain to cope with and adapt to stressful situations.

Sleep homeostasis is tightly linked to resilience, and the sleep deficits observed alongside neurodegeneration probably operate as direct drivers of neurodegeneration.

However, the knowledge gaps still remain huge and causally bridging the molecular/cellular with the behavioral and organismic level remains a challenge, hampering progress equally for biomedical and basic research.Our recent data suggest that a form of presynaptic active zone plasticity (PreScale), widely triggered in sleep-deprived Drosophila brains, can enhance the brain resilience to cope with the adverse effects of sleep deprivation.

Concretely, genetically fostering PreScale in sleepless mutants rescued them from their reduced lifetime, stress sensitivity, cognitive deficits and hyperexcitability due to too low levels of voltage-gated potassium channels.In SynProtect, we seek to test our hypothesis that PreScale constitutes a globally-operating homeostatic plasticity mechanism remodeling presynaptic terminals comprehensively to tune resilience states.In order to test this idea, we will elucidate the core molecular scenario executing and bidirectionally regulating PreScale and, consequently, decipher how exactly the remodeling of the mere presynaptic active zones and local excitability tuning via potassium channels intersect at the presynaptic terminal.

In parallel, we will test whether PreScale is needed to enhance resilience in a brainwide fashion or if its modus operandi is more local.

Genetic manipulation of PreScale will allow us to define brain states of high andlow resilience, which we will dissect combining super-resolution and in vivo activity imaging and proteomic tools.

Thus, we will open the way towards a comprehensive insight into the activity, signaling and metabolic profile of brain resilience.