Perinatal hypoxia is an important cause of brain injury amongst the newborn, such injury often resulting in an increased risk of impaired performance as regards learning and memory in later life for the affected individual. The postsynaptic density 95 (PSD-95) protein is a cytoskeletal specialization involved in the anchoring of N-methyl-D-aspartate (NMDA) receptors in postsynaptic neurons and has been reported to serve several important functions (e.g., synaptogenesis, synaptic plasticity and learning and memory performance) for the mammalian brain. Herein we investigated the long-term effects of perinatal hypoxia upon the complex of PSD-95 with NMDAR subunits by means of downstream signalling cAMP response element binding protein (CREB) phosphorylation at the Serine-133 locus (CREBSer-133 phosphorylation) within the hippocampal CA1 area (an essential integration area for mammalian learning and memory) within test-rat brains, as well as the effects upon afflicted-individual long-term learning and memory performance. We also assessed the therapeutic efficacy of dopamine D1/D5 receptor (D1/D5R) activation for such study animals. Perinatal hypoxia on postnatal day ten (P10) led to impaired performance as regards long-term spatial learning and memory (as determined on P45) associated with decreases in the level of CREBSer-133 phosphorylation and decreases in the expression of the complex of PSD-95 with NMDAR subunits (NR1, NR2A, and NR2B). In addition, activation of the D1/D5R via A68930 (a selective, CNS-permeable agonist of D1/D5Rs) administration (2 mg/kg/day, P17-23 inclusively) markedly attenuated the hypoxia-induced deleterious effects, suggesting an effective therapeutic efficacy for A68930. Our results demonstrate the long-term effects of perinatal hypoxia upon the developing brain and provide additional insights into the relative vulnerability of postsynaptic density (PSD) proteins to such insult, as well as the impairment of downstream transcription signalling CREBSer-133 phosphorylation following perinatal bypoxia. More importantly, D1/D5R activation following perinatal hypoxia may be an alternative therapeutic strategy to that which is currently available and may offer significant clinical potential for hypoxia sufferers. (c) 2006 Elsevier Inc. All rights reserved.

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 P 10 to P 14; 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 P 15 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 (pCREB(Ser-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 pCREB(Ser-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.