Yale researchers will use cellular imaging techniques in brain tissues of epilepsy patients, which have been surgically removed to treat medication-resistant seizures, to determine the cellular cause of slowed brain metabolism in epilepsy.
Epilepsy seizures occur when neurons in large areas of brain tissue fire synchronously. Paradoxically, while epilepsy is characterized by brain cell hyperactivity during a seizure, a consistent feature of epilepsy is a reduced metabolic rate, or “hypometabolism.” Research has focused on neurons that use the excitatory neurotransmitter glutamate to communicate with one another, and on cells called “astrocytes” that ordinarily clear away excess glutamate from the spaces (called synapses) where one neuron passes glutamate on to the next. Metabolic problems in the affected neurons might be involved. Or, if astrocytes fail to fully clear away glutamate, neurons may become overstimulated simultaneously and produce a seizure. The investigators hypothesize that malfunctioning astrocytes have defects in their mitochondria, the metabolic energy-producing engine of cells.
With initial Dana support, the Yale researchers demonstrated the feasibility of using multiphoton fluorescence microscopy in combination with fluorescence lifetime imaging to study mitochondria in astrocytes in brain tissues in an epilepsy animal model. Multiphoton imaging measures exactly how long it takes, after stimulating a molecule (called NADH) that is involved in energy metabolism in mitochondria, to emit fluorescence. Fluorescence lifetime imaging removes artifacts affecting interpretation of these results.
Now the investigators will use these imaging techniques in surgically removed brain tissue from epilepsy patients, to study NADH molecules in the mitochrondria of neurons and astrocytes. They expect to determine that astrocytic energetics are impaired, as determined by abnormal NADH lifetime distributions, while the surviving neurons are relatively normal in this regard.