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 occurred 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, we developed animal models for the spreading depolarization using zebrafish and mouse.

Evolutionary conservation of the spreading depolarization

Zebrafish is an animal model suitable for genetic study and drug screening, though it remains unclear how widely the spreading depolarization can be observed throughout the evolution of the vertebrate brain. We address this by examining the response of the zebrafish midbrain, the tectum to the chemical stimulation. Results showed that the zebrafish tectum exhibited long-lasting depression of the brain wave with transient increase of blood flow. This is mediated by NMDA-type glutamatergic receptors as judged from the fact that fish spreading depolarization was attenuated by blocker of NMDA-type glutamate receptor, MK-801. We are currently extending this finding to develop a drug screening system using zebrafish to identify a small molecule suppressing the spreading depolarization.

Terai H, Gwedela MNV, Kawakami K, Aizawa H. Electrophysiological and pharmacological characterization of spreading depolarization in the adult zebrafish tectum. J Neurophysiol. 2021 Dec 1;126(6):1934-1942. [FullText]

Cellular activation during initiation of the spreading depolarization

Brain structure primarily works with interplay between excitatory and inhibitory neurons. However, sequence of activation in these two distinct types of neurons remains elusive. We addressed this by applying multiple single unit recording to the mouse cerebral cortex. Electrophysiology revealed that the FS-type inhibitory neurons seemed to be upregulated earlier than the other type of cells such as excitatory neurons and the other inhibitory neurons, highlighting a role of inhibitory neurons in initiation of the spreading depolarization. Interestingly, the spreading depolarization induced immediate early gene expression c-Fos in parvalbumin-positive FS-type inhibitory neurons in the layer III and IV.

Handa T, Zhang Q, Ma Z, Aizawa H. Cell type-specific contribution to the initiation of cortical spreading depolarization in the mouse. Biochem Biophys Res Comm. 2025 751:151428 [FullText]

Neuro-glia interplay as a determinant of susceptibility to the spreading depolarization

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 depolarization. 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 depolarization with altered kinetics in extracellular glutamate. These results suggest that enhancement of the glutamate transporter in the astrocytes may suppress frequent spreading depolarization and improve neurological sequelae.

Aizawa H, Sun W, Sugiyama K, Itou Y, Aida T, Cui W, Toyoda S, Terai H, Yanagisawa M, Tanaka K. Glial glutamate transporter GLT-1 determines susceptibility to spreading depression in the mouse cerebral cortex. Glia. 2020 Dec;68(12):2631-2642. [FullText]

See also a recent post shown below.

New publication on spreading depression implicated in migraine!