Morphological and behavioral consequences of recurrent seizures in neonatal rats are associated with glucocorticoid levels

Abstract

Objective It is well documented that epilepsy can increase neurogenesis in certain brain regions and cause behavioral alternations in patients and different epileptic animal models. A series of experimental studies have demonstrated that neurogenesis is regulated by various factors including glucocorticoid (CORT), which can reduce neurogenesis. Most of studies in animal have been focused on adulthood stage, while the effect of recurrent seizures to immature brain in neonatal period has not been well established. This study was designed to investigate how the recurrent seizures occurred in the neonatal period affected the immature brain and how CORT regulated neurogenesis in immature animals. Methods Neonatal rats were subjected to 3 pilocarpine-induced seizures from postnatal day 1 to day 7. Then neurogenesis at different postnatal ages (i.e. P8, P12, P22, P50) was observed. Behavioral performance was tested when the rats were mature (P40), and plasma CORT levels following recurrent seizures were simultaneously monitored. Results Rats with neonatal seizures had a significant reduction in the number of Bromodeoxyuridine (BrdU) labeled cells in the dentate gyrus compared with the control groups when the animals were euthanized on P8 or P12 (P < 0.05); whereas there was no difference between the two groups on P22. Until P50, rats with neonatal seizures had increased number of BrdU-labeled cells compared with the control group (P < 0.05). In Morris water maze task, pilocarpine-treated rats were significantly slower than the control rats at the first and second day, and there were no differences at other days. In probe trial, there was no significant difference in time spent in the goal quadrant between the two groups. Endocrine studies showed a correlation between the number of BrdU positive cells and the CORT level. Sustained increase in circulating CORT levels was observed following neonatal seizures on P8 and P12. Conclusion Neonatal recurrent seizures can biphasely modulate neurogenesis over different time windows with a down-regulation at early time and up-regulation afterwards, cause persistent deficits in cognitive functions of adults, and increase the circulating CORT levels. CORT levels are related with the morphological and behavioral consequences of recurrent seizures.

Down-regulation of APLP1 mRNA expression in hippocampus of pilocarpine-induced epileptic rats

“…Epilepsy was an intractable neural disease with complex morphological changes in the brain, especially in hippocampus, such as hippocampal neuronal loss, mossy fiber sprouting and progressive development of neural circuit [14,15] . Researchers consistently noticed the marked decrease of dendritic spine density in hippocampal pyramidal cells, and abnormal spine shapes from human and animal epilepsy models [22][23][24][25][26] . Since APLP1 is highly expressed mainly in neuronal dendritic spine and postsynaptic density (PSD) [6,7] , it's proposed that the persistently low level of APLP1 expression seems to be consistent with the decrease of dendritic spine density in the epileptic neurons.…”

Adult Neurogenesis in Epileptogenesis: An Update for Preclinical Finding and Potential Clinical Translation

“…Interestingly, conflicting results were observed when evaluating adult neurogenesis in neonatal rats. In contrast to the increased cell proliferation observed after acute epileptogenic insults in adult animals, neurogenesis decreased after acute SE in young pups, and a modest increase in neurogenesis even at 2 months after SE was found [ 44 - 47 ]. Thus, it seems that the change of adult neurogenesis depends on the developmental state of the brain at the time of the initial seizure induction.…”

Fragile X syndrome and epilepsy

“…It can be produced by an imbalance between neuronal excitation and inhibition, where glutamate and γ-aminobutyric acid (GABA), respectively, play important roles. Furthermore, chronic experimental models of epilepsy and the phenomenon of kindling have provided abundant evidence that neural circuits undergo long-term progressive structural and functional alterations in response to seizures which maybe in turn leads to further epileptogenesis [14,15] . There is also considerable effort directed to the molecular changes that occur during epileptogenesis.…”