Induced Spreading Depression Activates Persistent Neurogenesis in the Subventricular Zone, Generating Cells With Markers for Divided and Early Committed Neurons in the Caudate Putamen and Cortex

Abstract

Background and Purpose-Status epilepticus and cerebral ischemia stimulate persistent neurogenesis in the adult brain, but both conditions cause neuronal damage. We determined whether spreading depression, a common epiphenomenon of these conditions, stimulates persistent neurogenesis. Methods-We analyzed the effect of KCl-induced spreading depression on persistent neurogenesis and the spatio-temporal distribution of cells exhibiting immunohistochemical markers for divided and early committed neurons (new neurons) in the adult rat brain. Results-After induction of spreading depression for 48 hours, the density of mitotic cells, divided cells, and new neurons in the subventricular zone increased at days 1 to 3, days 3 to 6, and day 6, respectively (PϽ0.05). The divided cell density in the rostral migratory stream and the stream size increased at day 12 (PϽ0.001). Vehicle (saline) infusion or induction of spreading depression for 4 hours only did not increase the divided cell density, but the latter increased new neuron density in the subventricular zone (PϽ0.001). Double-labeled new neuron-like cells also appeared in the caudate putamen or cortex in ectopic fashion at day 3, with dramatic increases at days 6 and 12. Administration of the NMDA receptor antagonist, MK-801, which inhibits the propagation of spreading depression, abolished the increase in new neurons in the subventricular zone and the appearance of ectopic new neuron-like cells after 48-hour KCl infusion. There was no neuronal damage, as evidenced by mature neuron density, neurite density, and apoptotic cell appearance after spreading depression for 48 hours. Conclusions-Spreading

Cortical Spreading Depression Shifts Cell Fate Determination of Progenitor Cells in the Adult Cortex

“…Although progenitor cells migrating from the SVZ (subventricular zone) were also a candidate for newborn astrocytes in the cerebral cortex. However, the BrdU-labeled cell density in the SVZ was not affected by SD induction (Yanamoto et al, 2005). This finding suggests that origin of the newborn cells in the cortex was unlikely to be progenitor cells in the SVZ.…”

Spreading Depolarization, A Pathophysiological Mechanism of Stroke and Migraine Aura

“…Spreading depolarizations have many adverse effects and it has been clearly shown in animals that they facilitate death when they invade metabolically compromised tissue [16,52,53,55], but they may also have beneficial effects in the surrounding healthy tissue where they may precondition, or promote plasticity or regeneration [121][122][123]. Unfortunately, it is more difficult to block spreading depolarization in more metabolically compromised tissue, and not vice versa.…”

Induced Spreading Depression Evokes Cell Division of Astrocytes in the Subpial Zone, Generating Neural Precursor-Like Cells and New Immature Neurons in the Adult Cerebral Cortex

“…4,5 Previously, we found that induced multiple SD waves in the adult rat brain under normal condition activates cell division of neural progenitor cells in the subventricular zone (SVZ), enhancing persistent neurogenesis toward the olfactory bulb. 6 Furthermore, induced SD generates new immature neurons, at an ectopic location, in cortical Layers V to VI. 6 Recently, it was found that induced SD activates neurogenesis in the hippocampal subgranular zone.…”