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Repeated carbenoxolone injection during late pregnancy decreased SPAR but increased Snk expression in the hippocampus of rat pups
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Poster Abstracts / Int. J. Devl Neuroscience 28 (2010) 655–719
tions presenting with hydrocephalus. The data we have obtained from the limited number of affected babies suggests a similar folate imbalance to that found in the rat model indicating that the human condition may also be amenable to the same combination folate supplements.Keywords: Hydrocephalus; Fetus; Cerebral cortex; Folate Reference: Cains, S., A. Shepherd, et al. (2009). “Addressing a folate imbalance in fetal cerebrospinal fluid can decrease the incidence of congenital hydrocephalus.” J. Neuropathol. Exp. Neurol. 68(4): 404–16. doi:10.1016/j.ijdevneu.2010.07.131 [P2.02] Repeated carbenoxolone injection during late pregnancy decreased SPAR but increased Snk expression in the hippocampus of rat pups N. Jutapakdeegul ∗ , P. achatyanukul
Surakul, R.
Vanichviriyakit, W.
Weer-
Mahidol University, Thailand Homeostasis of circulating cortisol is maintained by two enzymes of 11-hydroxysteroid dehydrogenase, 11-HSD1 and 11-HSD2. 11-HSD2 is NAD-dependent dehydrogenase that inactivates cortisol into cortisone. In addition, 11-HSD2 is abundantly expressed in the placenta where it protects the fetus from active maternal glucocorticoids. Administration of carbenoxolone (CBX), a powerful 11-HSD2 inhibitor, leads to an increased of fetal cortisol level and decreased plasma cortisone levels. Previous data showed that intrauterine environment plays crucial roles in determining hippocampal structure and function in later life. Exposure to high level of corticosteroid during pregnancy lead to a low birth weight offspring, increased risk of aged related memory and cognitive deficits, however, mechanism still unclear. We proposed that repeated CBX injections during late pregnancy may alter scaffolding proteins of NMDA receptor in the hippocampus of rat pups. Here we show that pregnant rats receiving CBX injections (30 mg/kg) during GD14-21 lead to a significant decreased of SPAR (spine Associated Rap Guanylate kinase activating protein) (p < 0.01) but significant increased of Snk (Serum inducible kinase) (p < 0.01) in the pup’s hippocampus at P40 and P60, while the level of PSD-95 remain unchanged. NMDA receptor function has been shown to be influenced by turnover of the scaffolding proteins via ubiquitin proteasome system (UPS). Normally, Snk is induced by neuronal activity and plays an important role in phosphorylate SPAR. The phosphorylated SPAR was then recognized and degraded by ubiquitin-proteasome system, causing the depletion of SPAR and PSD-95 from the spines and leading to spine shrinkage and loss. The results suggest that fetal exposure with excessive corticosteroids may activate Snk/SPAR pathway and lead to the depletion of SPAR. Since, corticosteroid drugs are commonly used in various obstetric and paediatric conditions, it is important to consider the risk–benefit of prenatal GC exposure to prevent the neurodevelopment delay in the offspring.Keywords: Carbenoxolone; SPAR; Snk; Hippocampus doi:10.1016/j.ijdevneu.2010.07.132
[P2.03] Repeated maternal restraint stress down-regulated NMDA receptor subunits and scaffolding proteins in the hippocampus of postnatal rat P. Surakul ∗ , R. Vanichviriyakit, W.A. Weerachatyanukul, N. Jutapakdeegul Mahidol University, Thailand Early life stress has been linked with a substantially increased risk of aged related memory and cognitive deficits. Maternal stress hormone plays a crucial role in determining pup’s hippocampal structure and function, however mechanism is still unclear. We proposed that prenatal stress (PS) may alter developmental expression of NR2A, NR2B subunits of NMDA receptor and its scaffolding proteins in the hippocampus of rat pups. To investigate this hypothesis, pregnant rats were restrained during late gestation (GD14-21) and the expression of NR2A, NR2B subunits, PSD-95 (Postsynaptic density protein-95), SPAR (sSpine associated Rap guanylate kinase activating protein) and Snk (Serum inducible kinase) were measured in the hippocampus of rat pups from P7–P60. First, we found that, PS pups show a significant decreased of NR2A and NR2B subunit at P40 (p < 0.001 and p < 0.05, respectively) and P60 (p < 0.01). Then we found that PS caused a significant increased of PSD-95 in the pup’s hippocampus during P7–P14 (p < 0.05) and P28 (p < 0.01), but decreased significantly at P40 (p < 0.001) and P60 (p < 0.01) as compare to control. The decreased of PSD-95 and NMDAR subunits can be explained by alteration of Snk-SPAR pathway. We also found that PS caused a significant increased of SPAR during P7 and P14 (p < 0.05), but showed a significant decreased during P40 (P < 0.001) and P60 (p < 0.01). The most interested finding is that PS pups show significant increased of Snk (P < 0.001) in the hippocampus throughout their childhood period from P7-P40 as compared to control. These data suggested that early life stress exert long term effects on the development of NMDAR in the pup’s hippocampus. Prenatal stress alters development of scaffolding proteins and NMDAR subunits may underlies the mechanism link between early life stress and increased risk of aged related memory and cognitive deficits and heightened vulnerability to psychological disorders in later life. Keywords: Prenatal stress; NMDA receptor; Scaffolding proteins; Hippocampus doi:10.1016/j.ijdevneu.2010.07.133 [P2.04] Using zebrafish to understand the neurodevelopment role of susceptibility genes for autism spectrum disorder B. Key University of Queensland, Australia Several studies in the last three years have revealed that members of a synaptic cell adhesion network are candidate susceptibility genes for Autism spectrum disorder (ASD). These genes include neurexin-1 (NRXN1), neuroligin-1 (NLGN1), NLGN4, contactin associated protein 2 (CNTNAP2 or previously known as CASPR2) and Shank3. ASD is increasingly attributed to a disorder of brain function rather than brain anatomy. We have begun to address the role of gene-gene interactions within the synaptic cell adhesion pathway involved in neural circuits associated with simple behaviours using the zebrafish animal model. We are focusing on interactions between identified susceptibility genes NLGN-1, NLGN-4, NRXN-1, Shank3 and CNTNAP2 as well as on interactions of these genes with other known synaptic cell adhe-
Poster Abstracts / Int. J. Devl Neuroscience 28 (2010) 655–719
tions presenting with hydrocephalus. The data we have obtained from the limited number of affected babies suggests a similar folate imbalance to that found in the rat model indicating that the human condition may also be amenable to the same combination folate supplements.Keywords: Hydrocephalus; Fetus; Cerebral cortex; Folate Reference: Cains, S., A. Shepherd, et al. (2009). “Addressing a folate imbalance in fetal cerebrospinal fluid can decrease the incidence of congenital hydrocephalus.” J. Neuropathol. Exp. Neurol. 68(4): 404–16. doi:10.1016/j.ijdevneu.2010.07.131 [P2.02] Repeated carbenoxolone injection during late pregnancy decreased SPAR but increased Snk expression in the hippocampus of rat pups N. Jutapakdeegul ∗ , P. achatyanukul
Surakul, R.
Vanichviriyakit, W.
Weer-
Mahidol University, Thailand Homeostasis of circulating cortisol is maintained by two enzymes of 11-hydroxysteroid dehydrogenase, 11-HSD1 and 11-HSD2. 11-HSD2 is NAD-dependent dehydrogenase that inactivates cortisol into cortisone. In addition, 11-HSD2 is abundantly expressed in the placenta where it protects the fetus from active maternal glucocorticoids. Administration of carbenoxolone (CBX), a powerful 11-HSD2 inhibitor, leads to an increased of fetal cortisol level and decreased plasma cortisone levels. Previous data showed that intrauterine environment plays crucial roles in determining hippocampal structure and function in later life. Exposure to high level of corticosteroid during pregnancy lead to a low birth weight offspring, increased risk of aged related memory and cognitive deficits, however, mechanism still unclear. We proposed that repeated CBX injections during late pregnancy may alter scaffolding proteins of NMDA receptor in the hippocampus of rat pups. Here we show that pregnant rats receiving CBX injections (30 mg/kg) during GD14-21 lead to a significant decreased of SPAR (spine Associated Rap Guanylate kinase activating protein) (p < 0.01) but significant increased of Snk (Serum inducible kinase) (p < 0.01) in the pup’s hippocampus at P40 and P60, while the level of PSD-95 remain unchanged. NMDA receptor function has been shown to be influenced by turnover of the scaffolding proteins via ubiquitin proteasome system (UPS). Normally, Snk is induced by neuronal activity and plays an important role in phosphorylate SPAR. The phosphorylated SPAR was then recognized and degraded by ubiquitin-proteasome system, causing the depletion of SPAR and PSD-95 from the spines and leading to spine shrinkage and loss. The results suggest that fetal exposure with excessive corticosteroids may activate Snk/SPAR pathway and lead to the depletion of SPAR. Since, corticosteroid drugs are commonly used in various obstetric and paediatric conditions, it is important to consider the risk–benefit of prenatal GC exposure to prevent the neurodevelopment delay in the offspring.Keywords: Carbenoxolone; SPAR; Snk; Hippocampus doi:10.1016/j.ijdevneu.2010.07.132
[P2.03] Repeated maternal restraint stress down-regulated NMDA receptor subunits and scaffolding proteins in the hippocampus of postnatal rat P. Surakul ∗ , R. Vanichviriyakit, W.A. Weerachatyanukul, N. Jutapakdeegul Mahidol University, Thailand Early life stress has been linked with a substantially increased risk of aged related memory and cognitive deficits. Maternal stress hormone plays a crucial role in determining pup’s hippocampal structure and function, however mechanism is still unclear. We proposed that prenatal stress (PS) may alter developmental expression of NR2A, NR2B subunits of NMDA receptor and its scaffolding proteins in the hippocampus of rat pups. To investigate this hypothesis, pregnant rats were restrained during late gestation (GD14-21) and the expression of NR2A, NR2B subunits, PSD-95 (Postsynaptic density protein-95), SPAR (sSpine associated Rap guanylate kinase activating protein) and Snk (Serum inducible kinase) were measured in the hippocampus of rat pups from P7–P60. First, we found that, PS pups show a significant decreased of NR2A and NR2B subunit at P40 (p < 0.001 and p < 0.05, respectively) and P60 (p < 0.01). Then we found that PS caused a significant increased of PSD-95 in the pup’s hippocampus during P7–P14 (p < 0.05) and P28 (p < 0.01), but decreased significantly at P40 (p < 0.001) and P60 (p < 0.01) as compare to control. The decreased of PSD-95 and NMDAR subunits can be explained by alteration of Snk-SPAR pathway. We also found that PS caused a significant increased of SPAR during P7 and P14 (p < 0.05), but showed a significant decreased during P40 (P < 0.001) and P60 (p < 0.01). The most interested finding is that PS pups show significant increased of Snk (P < 0.001) in the hippocampus throughout their childhood period from P7-P40 as compared to control. These data suggested that early life stress exert long term effects on the development of NMDAR in the pup’s hippocampus. Prenatal stress alters development of scaffolding proteins and NMDAR subunits may underlies the mechanism link between early life stress and increased risk of aged related memory and cognitive deficits and heightened vulnerability to psychological disorders in later life. Keywords: Prenatal stress; NMDA receptor; Scaffolding proteins; Hippocampus doi:10.1016/j.ijdevneu.2010.07.133 [P2.04] Using zebrafish to understand the neurodevelopment role of susceptibility genes for autism spectrum disorder B. Key University of Queensland, Australia Several studies in the last three years have revealed that members of a synaptic cell adhesion network are candidate susceptibility genes for Autism spectrum disorder (ASD). These genes include neurexin-1 (NRXN1), neuroligin-1 (NLGN1), NLGN4, contactin associated protein 2 (CNTNAP2 or previously known as CASPR2) and Shank3. ASD is increasingly attributed to a disorder of brain function rather than brain anatomy. We have begun to address the role of gene-gene interactions within the synaptic cell adhesion pathway involved in neural circuits associated with simple behaviours using the zebrafish animal model. We are focusing on interactions between identified susceptibility genes NLGN-1, NLGN-4, NRXN-1, Shank3 and CNTNAP2 as well as on interactions of these genes with other known synaptic cell adhe-