Anaerobic glycolysis modulates neuronal excitability
Skwarzynska, Daria, Neuroscience - School of Medicine, University of Virginia
Kapur, Jaideep
This dissertation describes the important role of anaerobic glycolysis-derived energy in seizure activity and a feedback mechanism to fine tune neuronal excitability through glycolysis-derived lactate and lactate receptor, HCA1R. We combined an enzyme-based lactate and glucose biosensor probes with video-EEG recordings, genetically-encoded calcium indicator 7, GCAMP7, patch-clamp electrophysiology and knock-out mice to study how anaerobic glycolysis regulates neuronal excitability.
We found that a single non-convulsive seizure and status epilepticus (SE) strongly stimulate anaerobic glucose metabolism, as extracellular glucose concentration rapidly drops and lactate accumulates in the extracellular space. We detected that high-and low-amplitude fast discharges are associated with increased glucose metabolism and lactate buildup in the extracellular space. The high-and low-amplitude fast discharges are more frequent in the first quarter of SE, which coincide with higher anaerobic glycolytic rate.
High dependency of glycolysis-derived energy to sustain seizure activity, indicate that targeting this metabolic pathway represents a promising therapeutic target to resolve seizures and SE. We found that oxamate, a lactate dehydrogenase inhibitor, effectively terminates experimental SE and reduces associated neuronal damage. Oxamate reduces neuronal excitability and inhibits the glutamatergic neurotransmission. Metabolic intermediates can alter neuronal firing properties by directly activating ligandgated ion channels, such as the KATP channel or G-protein coupled purinergic receptors.
We found that excessive neuronal activity associated with seizures accelerates glycolysis to generate lactate, which translocates to the extracellular to bind its specific receptor, hydroxycarboxylic acid receptor type 1 (HCA1R), also known as G-protein coupled receptor-81 (GPR81). Mice which lack HCA1Rare more susceptible to developing seizures and SE. Activation of HCA1R slowed neuronal firing and inhibits excitatory transmission in CA1 principal neurons in vitro. We propose a feedback mechanism to fine tune neuronal excitability through glycolysis-derived lactate and lactate receptor, HCA1R.
PHD (Doctor of Philosophy)
Glycolysis
English
All rights reserved (no additional license for public reuse)
2023/04/26