The effects of nitric oxide inhibition prior to kainic acid treatment on neuro- and gliogenesis in the rat dentate gyrus in vivo and in vitro.

Treatment with the nitric oxide synthase (NOS) inhibitor, L-NAME prior to the induction of seizures with kainic acid (KA) [L-NAME+KA] increases the expression of activity-dependent neuroprotective protein (ADNP) in cells in the subgranular zone (SGZ) of the rat dentate gyrus 3-days after seizure induction (Cosgrave et al., 2009). Using the incorporation of BrdU we found that this protocol [L-NAME+KA] stimulates neuro- and gliogenesis. By comparison, L-NAME or KA alone produced smaller effects. Doublecortin+ (BrdU negative) neuroblasts in the SGZ also significantly increased with L-NAME+KA treatment, suggesting that L-NAME+KA cause more cells to differentiate into neurons. L-NAME alone increased BrdU+ astrocytes in the hilus implying that NO inhibits stem cell differentiation into astrocytes and may also influence their migration. Although NOS inhibition increased cell proliferation in vivo and in vitro it disrupted cell clustering as revealed by ADNP immunoreactivity. In vitro KA treatment resulted in eccentric nuclei, reduced neurite extension and branching in neurons and retracted processes of glia cells, these changes were inhibited with prior treatment of L-NAME suggesting that KA-induced NO production affects cell morphology. Consequently, this data suggests an important role for NO in regulating stem cell proliferation and their fate in the SGZ.