Chloride homeostasis in neuronal compartments under acute metabolic stress

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In neurons, chloride gradients across the plasma membrane as well as across intracellular membranes serve multiple cellular functions, such as regulation of excitability, neurotransmitter release and pH and volume regulation. Chloride concentrations are determined via the interplay of various ion channels and secondary active transporters that couple anion concentrations to the electrochemical gradients of Na+, K+ and H+. Changes in [Na+], [K+] and [H+] during metabolic stress are thus expected to alter intracellular [Cl-]. We will study the chloride homeostasis in the neuronal soma and in neuronal extensions as well as in intracellular organelles under normal conditions and under metabolic stress. We will use fluorescence lifetime imaging microscopy with quinolinium-based fluorescent indicators or fluorescence imaging with genetically encoded chloride sensors as well as the electrophysiological analysis of reversal potentials of anion-selective channels. Cl- ions play an important role in regulating glutamate accumulation in synaptic vesicles of glutamatergic neurons, and we will study how glutamate and chloride concentrations modify each other. Cl-/H+ exchangers link [Cl-] and pH in endosomes, and we will analyze how pH regulation and chloride homeostasis are intertwined in these organelles under normal conditions as well as under energy restriction.