An imaging study on the contribution of glial energy metabolism to the neuroprotective effect of ketone bodies

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High circulating levels of ketone bodies are known to protect the brain tissue against intractable epilepsy, which amounts to a third of all clinical presentations of the disease. Ketone bodies also prevent seizures in glucose transporter difficiency syndrome and are important for brain development. The cellular and molecular mechanisms underlying the protective effect of ketone bodies are not clear and various hypothesis have been put forward proposing a role of neurons. The purpose of the present project is to investigate whether energy metabolism in glial cells also play a role in the protection. Data from several sources including our own previous collaborative effort has shown that glial cells are key mediators of neurometabolic coupling, producing lactate from glucose both under basal conditions and upon neuronal demand. Lactate is in turn used as energy fuel by neurons, which in addition metabolize glucose to keep their redox balance and avert apoptosis. In this scenario, the main hypothesis of the present project is that ketone bodies, which are efficient oxidative substrates, allow glial cells to reduce their oxidation of glucose thus sparing the sugar for neuronal usage. We will also explore the possibility that ketone bodies alter the usage of glucose by neurons. To these aims, we will take advantage of new imaging techniques developed by our groups, one of which allows estimation of the glycolytic rate in single cells with high temporal resolution using a FRET glucose nanosensor. The other technique is capable of estimating the contribution of specific cell types to the uptake and metabolism of sugars in tissue slices using fluorescent glucose analogues and multiphoton microscopy. We envisage that a mechanistic understanding of the protection by ketone bodies may help to disclose new therapeutic targets for neurological conditions like epilepsy.