Approximately 28 million members of the U.S. population are affected by migraine. Migraine frequently progresses from Episodic Migraine (EM) to Chronic Migraine (CM). Current investigations into the transition from EM to CM have focused on the potential of a physiological process called Spreading Depression (SD) and the potential influence of the innate immune system in modulating this transition. SD may lead to an increase in pain sensitivity associated with migraine headache. SD is believed to be the neurophysiologic basis of the sensory symptoms experienced during migraine aura. SD can be studied directly by examining SD in slice cultures of the hippocampus; hippocampal slice cultures maintain the normal cell-to-cell connections present in vivo and are therefore easily accessible models to study physiological events in the brain. The three main characteristics of SD include a period of electrical silence and a Direct Current (DC) change, which propagates at 3 mm/min. Using electrophysiological techniques, the effects of recurrent SD on rat hippocampal slice cultures were observed. Recurrent SD was defined as six to seven episodes of induced SD occurring within one hour. To induce SD in the slices, current is passed through the trisynaptic circuit of the hippocampus, which begins at the pyramidal neurons located in the dentate gyrus (a region of the hippocampus). Ideally, the electrical current flows from the bipolar stimulating electrode, stationed in the dentate gyrus, to the CA3 region of the hippocampus, and finally to the CA1 region. Information is recorded in the CA3 region using a recording electrode. The recordings are amplified to visualize SD. It was postulated that the progression of episodic to chronic migraine is due to reversible changes in neuronal excitability as a result of recurrent SD. If recurrent SD leads to an increase in excitability then it could be considered an upstream cause of chronic migraine. The change in excitability may be due to decrease in density of inhibitory receptors in the brain and an upregulation of excitatory receptors. GABAA receptors are inhibitory receptors and AMPA receptors are excitatory receptors. It has been observed that Tumor Necrosis Factor-alpha (TNF-alpha), a cytokine involved in the regulation of innate immune cells and cell signaling, causes an upregulation of AMPARs and a downregulation of GABAA receptors (Malenka, et al., 2005). Therefore, a decrease in GABA receptor density would support the hypothesis that TNF-alpha released during SD signals a cascade of events that lowers inhibition. Overall, the goals of this project were to determine whether or not it is “easier” to fire spreading depression in slices that had previously experienced SD and to decipher whether or not TNF-alpha is involved in lowering the current threshold to fire SD. Observations showed that the increase in susceptibility to SD is dependent on TNF-alpha signaling. Thus, the transformation of EM to CM may stem from migraine-induced alterations in innate cytokine signaling within brain.
Victoria Levasseur, ’11 Cedar Rapids, IA
Majors: Biochemistry and Molecular Biology, Spanish
Sponsor: Barbara Christie-Pope