Metabolically driven action potentials serve neuronal energy homeostasis and protect from reactive oxygen species

So-called spontaneous neuronal activity is a central hallmark of most nervous systems. Such non-causal firing is contrary to the tenet of spikes as a means of communication, and its origin and purpose remain unclear. Here, we propose that non-input driven firing can serve as a release valve to protect neurons from the toxic conditions arising in mitochondria from lower-than-baseline energy consumption. We built a framework of models that incorporate homeostatic control of metabolic products–ATP, ADP, and reactive oxygen species, among others–by way of changes in firing. Our theory can account for key features of neuronal activity observed in many experiments in studies ranging from ion channels function all the way to resting state dynamics. We propose an integrated, crucial role for metabolic spiking that bridges the gap between metabolic homeostasis and neuronal function. Finally, we make testable predictions to validate or falsify our theory. ### Competing Interest Statement The authors have declared no competing interest. * α KG : Alpha ketoglutarate α Syn : Alpha synuclein CoQH2/CoQ : Coenzyme Q (reduced/oxidized form) FADH2 : Flavin adenine dinucleotide (reduced) IP3 : Inositol 1,4,5-trisphosphate PIP2 : Phosphatidylinositol 4,5-bisphosphate 6PG : 6-P-gluconate Act.CoA : Acetyl coenzyme A ADP : Adenosine diphosphate ADPR : Adenosine diphosphate ribose AIS : Axon initial segment ALT : Alanine transaminase AMP : Adenosine monophosphate ANT : Adenine nucleotide translocator AOX : Alternative oxidase APC : Anaphase-promoting complex AST : Aspartate transaminase ATP : Adenosine triphosphate BBB : Blood brain barrier cAMP : Cyclic adenosine monophosphate Cit : Citric acid CMA : Co-chaperone mediated autophagy CV : Coeffecient of variance D C , D E , D V : Dopamine cytosolic, extracellular, vesicle DA-Q : Dopamine-derived quinones DAG : Diacyl glycerol DAT : Dopamine transporter DHAP : Dihydroxyacetone phosphate DHODH : Dihydroorotate dehydrogenase DOPAC : 3,4-dihydroxyphenylacetic acid DOPAL : 3,4-Dihydroxyphenylacetaldehyde ETC : Electron transport chain ETF : Electron-transferring flavoprotein F1,6BP : Fructose 1,6-bisphosphate F2,6BP : Fructose 2,6-bisphosphate F6P : Fructose 6-phosphate FETROS : Forward electron transport ROS G3P : Glycerol 3-phosphate G6P : Glucose 6-phosphate GA3P : Glyceraldehyde 3-phosphate GBA : Glucocerebrosidase GDH : Glutamate dehydrogenase GEF : Guanine nucleotide exchange factors GPCR : G protein-coupled receptors GPDH : Glycerol-3-phosphate dehydrogenase Gpe : external globus pallidus Gpi : internal globus pallidus GS : Glutamine synthetase GSH : Glutathione (reduced) GSSH : Glutathione disulphide (oxidized) GTP : Guanosine triphosphate HEX : Hexokinase HK1 : Hexokinase-1 enzyme HSC70 : Heat shock cognate 71 kDa protein IDH : Isocitrate dehydrogenase ISI : Interspike interval LDH1/5 : Lactate dehydrogenase type 1 or 5 LRRK2 : Leucine-rich repeat kinase 2 MCU : Mitochondrial calcium uniporter ME : Malic enzyme MIM : Mitochondrial inner membrane miniSOG : small and efficient singlet oxygen generator MOM : Mitochondrial outer membrane MPP+ : 1-methyl-4-phenylpyridinium MS : Metabolic signal NADH/NAD+ : Nicotinamide adenine dinucleotide (reduced/oxidized) NADPH/NADP+ : Nicotinamide adenine dinucleotide phosphate (reduced/oxidized) NCX : Sodium calcium exchanger Oxa : Oxaloacetate PC : Pyruvate carboxylase PDH : Pyruvate dehydrogenase PDK4 : Pyruvate dehydrogenase kinase 4 PDP : Pyruvate dehydrogenase phosphatase PEP : Phosphoenolpyruvic acid PEPCK : Phosphoenolpyruvate carboxykinase PFK : Phosphofructokinase PFKFB3 : 6phosphofructo2kinase/fructose2,6biphosphatase3 PINK1 : PTEN-induced kinase 1 PKA : Protein kinase A PKC : Protein kinase C PKM1 : Pyruvate kinase M1 PLC : Phospholipase C PPP : Pentose phosphate pathway R5P : Ribose 5-phosphate RETROS : Reverse electron transport ROS ROS : Reactive oxygen species SCNA : Alpha synuclein SNcDA : Substantia nigra pars compacta dopaminergic neuron SNr : Substantia nigra pars reticulata SOD2 : Superoxide dismutase STN : Subthalamic nucleus TCA : Tricarboxylic acid TXN : Thioredoxin UCP : Uncoupler protein USP : Ubiquitin-specific protease V-ATPase : Vacuolar-type ATPase VMAT2 : Vesicular monoamine transporter 2