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.
OBJECTIVE
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 (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.


CONCLUSIONS
Spreading depression has the potential to stimulate persistent neurogenesis or to produce ectopic new neuron-like cells.
Yanamoto
Hiroji
H
Laboratory for Cerebrovascular Disorders, Research Institute of National Cardiovascular Center, Japan. hyanamot@res.ncvc.go.jp
Miyamoto
Susumu
S
Tohnai
Norimitsu
N
Nagata
Izumi
I
Xue
Jing-Hui
JH
Nakano
Yoshikazu
Y
Nakajo
Yukako
Y
Kikuchi
Haruhiko
H
D000818:Animals; D000963:Antimetabolites / Q000494:pharmacology; D017209:Apoptosis; D015415:Biomarkers / Q000737:chemistry*; D001921:Brain / Q000378:metabolism; D002545:Brain Ischemia / Q000473:pathology; D001973:Bromodeoxyuridine / Q000494:pharmacology; D002454:Cell Differentiation; D002455:Cell Division; D002490:Central Nervous System / Q000473:pathology; D002540:Cerebral Cortex / Q000378:metabolism*; D013181:Cortical Spreading Depression; D016291:Dizocilpine Maleate / Q000494:pharmacology; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D008564:Membrane Potentials; D018613:Microscopy, Confocal; D009474:Neurons / Q000378:metabolism / Q000473:pathology*; D011189:Potassium Chloride / Q000494:pharmacology; D011699:Putamen / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors; D013226:Status Epilepticus / Q000473:pathology; D013234:Stem Cells / Q000378:metabolism; D013997:Time Factors
D000963:Antimetabolites; D015415:Biomarkers; D005904:Glial Fibrillary Acidic Protein; D016194:Receptors, N-Methyl-D-Aspartate; D011189:Potassium Chloride; D016291:Dizocilpine Maleate; D001973:Bromodeoxyuridine