Prolonged Seizures Increase Proliferating Neuroblasts in the Adult Rat Subventricular Zone–Olfactory Bulb Pathway

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Abstract
Neuronal precursors in the adult rodent forebrain subventricular zone (SVZ) proliferate, migrate to the olfactory bulb in a restricted pathway known as the rostral migratory stream (RMS), and differentiate into neurons. The effects of injury on this neurogenic region of the mature brain are poorly understood. To determine whether seizure-induced injury modulates SVZ neurogenesis, we induced status epilepticus (SE) in adult rats by systemic chemoconvulsant administration and examined patterns of neuronal precursor proliferation and migration in the SVZ–olfactory bulb pathway. Within 1–2 weeks after pilocarpine-induced SE, bromodeoxyuridine (BrdU) labeling and Nissl staining increased in the rostral forebrain SVZ. These changes were associated with an increase in cells expressing antigenic markers of SVZ neuroblasts 2–3 weeks after prolonged seizures. At these same time points the RMS expanded and contained more proliferating cells and immature neurons. BrdU labeling and stereotactic injections of retroviral reporters into the SVZ showed that prolonged seizures also increased neuroblast migration to the olfactory bulb and induced a portion of the neuronal precursors to exit the RMS prematurely. These findings indicate that SE expands the SVZ neuroblast population and alters neuronal precursor migration in the adult rat forebrain. Identification of the mechanisms underlying the response of neural progenitors to seizure-induced injury may help to advance brain regenerative therapies by using either transplanted or endogenous neural precursor cells.