The brain is one of the major energy consumers of the human body. Conditions under which the brain’s energy demands exceed its availability, referred to as metabolic stress, give rise to rapid functional changes. An extreme form of metabolic stress is caused by brain ischemia, which can result in tissue damage and severe neurological deficits and which represents one of the leading causes of disability and death in our ageing population. The main mechanisms of delayed cell death, including the so-called "excitotoxic" action of the transmitter glutamate, are well described. In contrast, there are significant gaps in our understanding of the early changes in neuronal and glial function during reduced energy availability. As these synaptic changes are among the earliest and most "upstream" events in the ischemic cascade, a better understanding of what causes metabolic stress in synapses during ischemia is translationally relevant.
The Research Unit (RU) “Synapses under stress: Early events induced by metabolic failure at glutamatergic synapses” will close this gap and will combine molecular biology, biochemistry, imaging, electrophysiology and optogenetic approaches together with mathematical simulations to unravel the dependence of synaptic function on cellular metabolism. We will address acute changes in ion concentrations, transmitter homeostasis, as well as the function and the subcellular distribution of ligand- and voltage-gated ion channels which control electrical and chemical signaling. The consortium will analyse the major cellular components of glutamatergic synapses, i.e. pre- and postsynaptic neuronal compartments as well as perisynaptic astrocytes. We will focus on glutamatergic synapses of the mouse cortex as a joint model system and use a common protocol for induction of transient chemical ischemia. Adaptive and pathological processes will be addressed at the molecular, cellular and systems’ level, employing experimental systems of increasing complexity that range from primary cell culture to acute and organotypic tissue slices to in vivo models of ischemic stroke. Experimental results will be integrated into a computational model, which will provide a novel, concerted view on early functional changes of synapses under stress. We expect that our research programme will lead to a thorough understanding of immediate responses of the tripartite synapse to transient energy shortage, of their functional consequences, as well as of the potential reversibility of the induced effects. This will generate a new, integrative view of basic pathomechanisms of metabolic failure, which is urgently needed to develop better therapeutic strategies to combat stroke-induced brain damage.