Maternal Deprivation Stress Exacerbates Cognitive Deficits in Immature Rats with Recurrent Seizures

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Abstract
Summary: Purpose: Maternal deprivation is stressful for the neonate. The aim of this study was to investigate the short‐ and long‐term effects of maternal separation on recurrent seizures in the developing brain. Methods: Rats were divided into four groups according to whether the rat pups were treated with maternal deprivation from postnatal day 2 (P2) to P9 or neonatal seizures induced by intraperitoneal (i.p.) injection of pentylenetetrazol (PTZ) from P10 to P14. Rats in the control group received saline i.p. injection from P10 to P14; rats in the isolation group underwent daily separation from their dams from P2 to P9; rats in the PTZ‐treated group were subjected to PTZ‐induced recurrent seizures from P10 to P14; rats in the isolation plus PTZ–treated group were subjected to maternal deprivation from P2 to P7 followed by serial seizures from P10 to P14. In addition, subsets of rats at P15 were killed and the brains assessed for acute neuronal degeneration. Visual–spatial memory test using the Morris water maze task was performed at P80. After testing, the hippocampus was evaluated for histologic lesions and cyclic adenosine monophosphate (cAMP)‐responsive element‐binding protein phosphorylation at serine‐133 (pCREBSer‐133), an important transcription factor underlying learning and memory. Results: All rats given PTZ developed recurrent seizures. After PTZ administration, rats with a history of maternal deprivation had more intense impairment than did rats with maternal deprivation and neonatal seizures than those without deprivation. Neuronal degeneration was most prominent in the rats exposed to maternal deprivation plus recurrent seizures. Rats receiving maternal deprivation or PTZ‐induced recurrent seizures exhibited only spatial deficits, but no morphologic changes in the hippocampus. However, rats with maternal deprivation plus PTZ‐induced recurrent seizures exhibited worse visual–spatial learning compared with rats with either isolation or PTZ‐induced recurrent seizures alone. The levels of pCREBSer‐133 may play a role in the decrease in the hippocampus from the rats subjected to maternal deprivation and/or PTZ‐induced recurrent seizures, as compared with rats exposed to vehicle‐control saline. These results indicate that repeated maternal deprivation can exacerbate long‐term cognitive deficits resulting from neonatal seizures. In addition, impaired phosphorylation of CREBSer‐133. Conclusions: Repeated maternal deprivation stress has synergistic effects with recurrent seizures in inducing neurologic damage in the developing brain.