Using Insect Model Systems to Study Mechanisms of Spreading Depression
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Spreading depression (SD) occurs as a slowly propagating wave of neural inactivity and plays an important role in both the vertebrate and invertebrate CNS. Mammalian SD is associated with human pathologies such as migraine, stroke and traumatic brain injury while SD in the insect nervous system is involved in environmental stress-induced neural shutdown. Despite obvious differences in the design of the vertebrate and invertebrate CNS evidence suggests that the cellular mechanisms underlying mammalian and insect SD are conserved. In my thesis I investigated mechanisms of SD in the CNS of Locusta migratoria and demonstrate its occurrence in the brain of Drosophila melanogaster. I show that increases in neural activity heighten susceptibility to SD while reductions in activity are inhibiting, demonstrating that SD in the locust is strongly dependent on existing levels of neural activity. Additionally, my work demonstrated that glial cells play a critical role during locust SD. I show that treatments that inhibit glial spatial buffering or that disrupt the perineurial cells (specialized glia) of the blood-brain barrier exacerbate SD. Moreover, I found that SD induced under hypotonic conditions was associated with shorter latencies to onset, greater ionic disturbances and faster propagation rates compared to SD induced under hypertonic conditions. The results suggest that hypotonic-induced cell swelling promotes the accumulation of extracellular K+ ions ultimately promoting SD initiation. Indeed, reducing the accumulation of extracellular K+, either by limiting cell swelling or by inhibition of voltage-gated K+ channels, was found to protect against SD development. Lastly, I demonstrate that SD can be reliably induced and monitored in the brain of Drosophila melanogster. I characterized fly SD and show that different genetic strains vary in their vulnerability to the ionic disturbance. Overall, the results from my locust experiments led to a better characterization of invertebrate SD which was important at substantiating previously proposed models. My work also expanded on the comparative similarities between invertebrate and vertebrate SD providing further evidence that insect SD is a useful model for mammalian SD. Furthermore, I provided a new model system, the fly brain, on which control mechanisms involved in SD can be genetically dissected.