Neural excitability in stroke and migraine

Excitatory neural transmission is primarily mediated by glutamate in the synapse. However, excess extracellular glutamate is rather harmful for the brain and sometimes worsens brain pathology in neurological disorders such as stroke and migraine. Such pathological activation of neural tissue some can be propagated like waves in the brain and affect the prognosis of those diseases.

The ischemic and hypoglycemic brain, in particular, has an increase in neural excitability and shows propagation of neuronal and glial depolarization, a phenomenon known as spreading depolarization (spreading depression). Lesion core with hypoxia, for example, releases excitatory molecules such as glutamate and potassium. These molecules diffuse outside the cells and, in turn, activate the neurons surrounding the lesion core. Propagation of such an excitatory wave results in further demand of energy essential to maintain the viability of the tissue at risk surround the lesion core.

Indeed, recent studies frequently reported that spreading depolarization occured in the cerebral cortex of the patients with stroke and migraine. To make matters worse, a report revealed that the prognosis in the patients with traumatic brain injury was negatively correlated with the number of spreading depolarization observed in a given period.

Thus, therapeutic intervention to suppress spreading depolarization will be in need to improve sequelae in stroke. To address this, Professor Kohichi Tanaka (Tokyo Medical and Dental University) and I focused on a role of the glial cells in the brain. Glial cells such as astrocytes act to determine levels of glutamate concentration outside cells. Since astrocytes regulate the extracellular glutamate level by the glutamate transporter which uptakes the extracellular glutamate, we hypothesize that glutamate transporter activity in the astrocytes determines a susceptibility of the brain to spreading depression. Recent analyses revealed that mutant mice lacking glutamate transporter GLT-1 in a subset of astrocytes in the cerebral cortex had increased sensitivity to spreading depression with altered kinetics in extracellular glutamate.

These results suggest that enhancement of the glutamate transporter in the astrocytes may suppress frequent spreading depression and improve neurological sequelae.

See details in the recent post.

New publication on spreading depression implicated in migraine!