Dynorphin up-regulation in the dentate granule cell mossy fiber pathway following chronic inhibition of GluN2B-containing NMDAR is associated with increased CREB (Ser 133) phosphorylation, but is independent of BDNF/TrkB signaling pathways.
Dynorphin up-regulation in the dentate granule cell mossy fiber pathway following chronic inhibition of GluN2B-containing NMDAR is associated with increased CREB (Ser 133) phosphorylation, but is independent of BDNF/TrkB signaling pathways.
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DOI：
10.1016/j.mcn.2014.04.002
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发表时间：
2014-05
期刊：
影响因子：
--
通讯作者：
Bausch SB
中科院分区：
文献类型：
--
作者：
Rittase WB;Dong Y;Barksdale D;Galdzicki Z;Bausch SB
新出现的证据表明，神经元对N-甲基-D-天冬氨酸（NMDAR）激活/失活的反应受亚基组成的影响。例如，突触NMDAR（由GluN 2A> GluN 2B组成）的激活使cAMP反应元件结合蛋白（CREB）在Ser 133处磷酸化，诱导BDNF表达并促进神经元存活。突触外NMDAR（由GluN 2 B> GluN 2组成）的激活使CREB（Ser 133）去磷酸化，减少BDNF表达并触发神经元死亡。这些结果使我们假设，慢性抑制含GluN 2B的NMDAR将增加CREB（Ser 133）磷酸化，增加BDNF水平，随后改变下游强啡肽（DYN）和神经肽Y（NPY）的表达。我们专注于DYN和NPY，因为这些神经肽可以减少兴奋性神经传递和癫痫发作的发生，我们以前曾报道过，在长期使用GluN 2B拮抗剂治疗后，癫痫样事件减少。与我们的假设一致，用GluN 2B选择性拮抗剂ifenprodil或Ro 25，6981对海马切片培养物进行慢性处理（17-21天）增加CREB（Ser 133）磷酸化和颗粒细胞苔藓纤维途径DYN表达。用非亚型选择性NMDAR拮抗剂D-APV或美金刚胺进行类似处理对CREB（Ser 133）磷酸化或DYN表达均无显著影响。与我们的假设相反，用Ro 25，6981长期治疗后BDNF水平降低，但不是艾芬地尔，D-APV或美金刚。阻断BDNF的作用和TrkB的激活并没有显著增加在媒介物处理的培养物中的肺门DYN表达，并且在Ro 25，6981处理的培养物中没有影响。这些发现表明，慢性暴露于GluN 2B选择性NMDAR拮抗剂通过pCREB依赖性但BDNF/TrkB非依赖性机制增加DYN表达。
Emerging evidence suggests that neuronal responses to N-methyl-d-aspartate (NMDAR) activation/inactivation are influenced by subunit composition. For example, activation of synaptic NMDAR (comprised of GluN2A > GluN2B) phosphorylates cAMP-response-element-binding protein (CREB) at Ser 133, induces BDNF expression and promotes neuronal survival. Activation of extrasynaptic NMDAR (comprised of GluN2B>GluN2), dephosphorylates CREB (Ser 133), reduces BDNF expression and triggers neuronal death. These results led us to hypothesize that chronic inhibition of GluN2B-containing NMDAR would increase CREB (Ser 133) phosphorylation, increase BDNF levels and subsequently alter downstream dynorphin (DYN) and neuropeptide Y (NPY) expression. We focused on DYN and NPY because these neuropeptides can decrease excitatory neurotransmission and seizure occurrence and we reported previously that seizure-like events are reduced following chronic treatment with GluN2B antagonists. Consistent with our hypothesis, chronic treatment (17-21 days) of hippocampal slice cultures with the GluN2B-selective antagonists ifenprodil or Ro25,6981 increased both CREB (Ser 133) phosphorylation and granule cell mossy fiber pathway DYN expression. Similar treatment with the non-subtype-selective NMDAR antagonists D-APV or memantine had no significant effect on either CREB (Ser 133) phosphorylation or DYN expression. In contrast to our hypothesis, BDNF levels were decreased following chronic treatment with Ro25,6981, but not ifenprodil, D-APV or memantine. Blockade of BDNF actions and TrkB activation did not significantly augment hilar DYN expression in vehicle-treated cultures and had no effect in Ro25,6981 treated cultures. These finding suggest that chronic exposure to GluN2B-selective NMDAR antagonists increased DYN expression through a putatively pCREB-dependent, but BDNF/TrkB-independent mechanism.
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