Nitric Oxide Regulates Neurogenesis in the Hippocampus following Seizures

Abstract

Hippocampal neurogenesis is changed by brain injury. When neuroinflammation accompanies injury, activation of resident microglial cells promotes the release of inflammatory cytokines and reactive oxygen/nitrogen species like nitric oxide (NO). In these conditions, NO promotes proliferation of neural stem cells (NSC) in the hippocampus. However, little is known about the role of NO in the survival and differentiation of newborn cells in the injured dentate gyrus. Here we investigated the role of NO following seizures in the regulation of proliferation, migration, differentiation, and survival of NSC in the hippocampus using the kainic acid (KA) induced seizure mouse model. We show that NO increased the proliferation of NSC and the number of neuroblasts following seizures but was detrimental to the survival of newborn neurons. NO was also required for the maintenance of long-term neuroinflammation. Taken together, our data show that NO positively contributes to the initial stages of neurogenesis following seizures but compromises survival of newborn neurons.

RETRACTED ARTICLE: Inhibiting the microglia activation improves the spatial memory and adult neurogenesis in rat hippocampus during 48 h of sleep deprivation

“…Neuronal and glial cells interact with each other to maintain the brain homeostasis and integrate to promote the neurogenesis and memory processes [ 3 – 5 ]. Normally, glial cells exist in resting state, but under stress or pathological conditions, they become activated and increase the release of the pro-inflammatory molecules causing neuroinflammation that is detrimental to neurogenesis and further impair spatial memory [ 6 , 7 ].…”

Calpastatin Overexpression Preserves Cognitive Function Following Seizures, While Maintaining Post-Injury Neurogenesis

“…Interestingly, evidence of increased cell proliferation has also been observed in the hippocampus of patients with temporal lobe epilepsy (Blümcke et al, 2001 ; Crespel et al, 2005 ). In the model used by our group, the peak of cell proliferation in the DG was shown to occur on day 5 after seizure induction, with a significant increase in neuroblast migration after 14 days (Carreira et al, 2015 ), results that we were able to replicate in the present work. This heavy enhancement of early neurogenesis indicates that the microenvironment in the hippocampus not long after seizures is extremely pro-neurogenic, which makes it difficult for changes due to altered levels of calpain activity to be observed.…”

“…The KA model of brain lesion is thus often used for research involving hippocampal damage, especially in studies of temporal lobe epilepsy (Levesque and Avoli, 2013 ). It is also a good model for investigating hippocampal injury and its consequences (Araújo et al, 2008 ; Carreira et al, 2010 , 2015 ). Since the hippocampus is the main structure involved in learning and memory, it is not surprising that treatment with KA in rodents can induce cognitive impairment (Stubley-Weatherly et al, 1996 ), which has also been reported in patients with temporal lobe epilepsy (Hattiangady and Shetty, 2008 ).…”

“…In order to investigate neuroblast migration after lesion, WT and hCAST mice were given either KA or SAL (6–9 animals per group) and sacrificed by transcardial perfusion, after 14 days (Figure 1G ), when an increase in cell migration is known to occur in the DG after KA treatment (Carreira et al, 2015 ). Cell migration in the DG was then assessed by analyzing neuroblast staining with doublecortin (DCX), as described further in more detail.…”

“…For the quantification of newborn neurons, the percentage of cells labeled for both EdU and NeuN was determined in a total of up to 50 EdU-positive cells (Carreira et al, 2015 ) in the DG of eight animals per group, in images (orthogonal reconstructions of projections from 0.73 μm z-stacks) acquired in a LSM710 (Zeiss, Jena, Germany).…”