Published Online
on June 2, 2005

A more recent version of this article appeared on July 1, 2005

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Submitted on January 10, 2005
Revised on February 25, 2005
Accepted on March 21, 2005

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

Hiroji Yanamoto MD, DMSc^*; Susumu Miyamoto MD, DMSc; Norimitsu Tohnai PhD; Izumi Nagata MD, DMSc; Jing-Hui Xue MD, PhD; Yoshikazu Nakano BSc; Yukako Nakajo MSc; and Haruhiko Kikuchi MD, DMSc

From the Laboratory for Cerebrovascular Disorders (H.Y., N.T., J.-H.X., Y.N., Y.Nakajo), Research Institute of the National Cardiovascular Center, Department of Cerebrovascular Surgery (H.Y., S.M., I.N.), Hospital of the National Cardiovascular Center (H.K.), Japan; and the Laboratory for Basic Science (Y.Nakajo), Rakuwakai Otowa Hospital, Kyoto, Japan.

^* To whom correspondence should be addressed. E-mail: hyanamot{at}res.ncvc.go.jp.

Abstract--Status epilepticus and cerebral ischemia stimulate persistent neurogenesis in the adult brain, but both conditions cause neuronal damage. Spreading depression is a common epiphenomenon of these neurogenesis-stimulating conditions. 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. 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 (P<0.05). The divided cell density in the rostral migratory stream and the stream size increased at day 12 (P<0.001). 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 (P<0.001). 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. Spreading depression has the potential to stimulate persistent neurogenesis or to produce ectopic new neuron-like cells.

Key words: cell differentiation • cell division • membrane potential • progenitor cells

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