1. 20100875 JunGu Cho

2. Cortical spreading depression Cortical spreading depression(CSD) is a slowly propagating wave of rapid, near-complete depolarization of brain cells that lasts for about 1 minute and silences brain electrical activity for several minutes. It is characterized by the collapse of ion homeostasis, profound disruption of transmembrane ionic gradients and the release of neurotransmitters and other molecules from cellular compartments.

3. Spreading depolarization Spreading depolarization is abrupt, near-complete sustained depolarization of neurons and massive redistribution of ions, and propagate at a similar rate to CSD In spreading depolarization, restoration of the ionic gradients, repolarization and recovery of brain function occur with a prolonged time course compared with CSD or do not occur at all

4. CSD and spreading depolarization CSD to refer to the propagating depolarization that is followed by suppression of spontaneous activity and that is evoked in normally metabolizing brain tissue Spreading depolarization for all propagating depolarizations that are induced within brain tissue with differing degrees of metabolic impairment and/or inhibition of neuronal and glial (Na+K)ATPases, and ranging from mild, CSD-like spreading depolarizations to anoxic depolarization, which occurs when the metabolic impairment is near-complete

5. CSD depolarization and associated ionic changes

6. In early phase, the apical dendrites are almost completely depolarized while the soma is only partially depolarized. In main phase, apical dendrites and soma are completely depolarized. In late phase, only narrow-band in the dendrites remains completely depolarization.(this is followed by restricting net inward current to a narrow band in the apical dendrites)

7. CSD depolarization and associated ionic changes Changes in the extracellular concentrations of ions and of glutamate during CSD depolarization are shown. The CSD depolarization and associated ionic changes are assumed to propagate across the cerebral cortex from right to left. CSD propagation is mainly mediated by diffusion of K+ in the extracellular space.

8. Cerebral blood flow and metabolic changes Cerebral blood flow and brain metabolism are tightly coupled, as brain blood flow rises with an increasing demand for oxygen and glucose. As ATP is used to restore ionic gradient and to repolarize the membrane potential, CSD is associated with a large increase in energy metabolism and therefore a large transient increase in cerebral blood flow.

9. Mechanism(CSD initiation)

10. Generation of a net self-sustaining inward current across the membrane is necessary to initiate the positive feedback cycle. The net inward current leads to membrane depolarization and the release of K+ into the restricted interstitial space The leads to further activation of voltage-gated and/or [K+]-dependent channels, further depolarization and an increase in local [K+]

11. Mechanism(CSD initiation) This is the case of CSD induced by a brief K+ pulse or by electrical stimulation Voltage-gated Ca2+ channel activates, and glutamate is released from cortical pyramidal cell synapse NMDAR activates and make further depolarization

12. Mechanisms The number of + symbols indicates the degree of blockade of CSD or spreading depolarization initiation(or propagation) after complete pharmacological block. ++++ indicates complete block; ND, not determined

13. Mechanism Which element play important role in CSD? NMDAR 1)Put the pharmacological antagonist of NMDAR into brain 2)Check whether NMDAR antagonist block CSD or not 3)In the cerebral cortex and cortical slices, NMDAR antagonists completely block CSD even when the intensity of stimulation is several times larger than threshold NMDARs are necessary for CSD propagation.

14. Mechanisms(Propagation of CSD) The typical slow rate of CSD propagation implies that it is mediated by the diffusion of a chemical substance 1)Flooding of K+ and glutamate into the extracellular space during CSD 2)Both K+ and glutamate may mediate CSD propagation by diffusing into contiguous grey matter 3)They initialize the positive feedback cycle in adjacent cells Most evidence points to K+ rather than glutamate as the relevant diffusing substance

15. Mechanisms

16. Typical membrane potential(Vm) and extracellular potential(Vo) changes induced in a brain slice by hypoxia or oxygen-glucose deprivation(OGD) During anoxic depolarization, the extracellular ionic changes are similar to ionic changes in CSD After anoxic depolarization initiation, the tissue is rapidly re-oxygenated to enable membrane repolarization and restoration of ion gradients.

17. Mechanisms An anoxic depolarization initiation mechanism, in which the net self- sustaining inward current in the positive feedback cycle that ignites anoxic depolarization is mediated by multiple ion channels. NMDARs are the key ion channels that mediate most rather than other ion channels.

18. Mechanism(sustained depolarization phase during CSD and spreading depolarization) Neuronal depolarization during CSD and Spreading depolarization is mainly maintained by Na+ influx through non- selective cationic channels. (The identity of this channel remains incompletely understood) There is pharmacological evidence that activation of NMDARs contributes to the sustained depolarization phase of CSD and anoxic depolarization.

19. Implication Migraine Headache disorder with throbbing pain, nausea, vomiting and sensitivity to light and sound that lasts for 12-72 hours. Link between CSD and migraine. The discovery that certain genetic mutations cause one type of migraine, increase the risk of migraine aura in humans and facilitate CSD in mouse models. CSD activates the trigeminovascular system in animal models to cause headache. Prophylactic drugs raise the electrical and KCl thresholds to evoke CSD as a mechanism of prevention.

20. Conclusion Propagating depolarization is perpetrators of tissue injury within the compromised brain and in the genesis of migraine aura. NMDARs are the key dendritic channels for CSD initiation. Relationship of NMDARs and spreading depolarization is less clear. It need to develop drugs that effectively target CSD or spreading depolarization initiation and propagation to prevent and limit migraine aura as well as to mitigate the chaos and commotion.