New pathways driving sodium dysregulation under acute metabolic stress

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Intracellular Na+ homeostasis in the brain is strictly dependent on an intact energy metabolism. An increase in the intracellular Na+ concentration is thus an immediate and prime consequence of energy deprivation. Notwithstanding its pivotal role, the consequences of restricted energy supply on the Na+ concentration of neurons and astrocytes, the cellular mechanisms of Na+ overloading, its pathological relevance, as well as the specific role of astrocytes herein, are only partly understood. In the present project, we address these questions at glutamatergic synapses of the mouse brain in situ and in vivo and in human cells. To this end, we will employ fluorescence-based dynamic imaging of Na+ combined with electrophysiology to determine changes in Na+ in neurons and astrocytes under acute metabolic stress. Our aim is to identify the different pathways driving Na+ dysregulation, to analyse their interplay and to study their relevance in the pathogenesis of synaptic malfunction and cellular damage during restricted energy supply. Based on results obtained in the first funding period, we will focus on TRPV4 channels as newly identified pathways for Na+ loading (objective 1). Moreover, we will complement our work on the relevance of Na+-dependent acid-base transporters and aim to establish targeted delivery of drugs to ischemic areas guided by extracellular acidification (objective 2). Finally, we will study effects of energy depletion on brain organoids and organoid slice cultures derived from human iPSCs (objective 3). Our project will thus provide highly relevant information about the mechanisms of early Na+ dysregulation and the first steps and events triggering synaptic malfunction upon metabolic failure.