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首页> 外文期刊>The European Journal of Neuroscience >Lack of PSD-95 drives hippocampal neuronal cell death through activation of an alpha CaMKII transduction pathway.
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Lack of PSD-95 drives hippocampal neuronal cell death through activation of an alpha CaMKII transduction pathway.

机译：缺乏PSD-95会通过激活αCaMKII转导途径来驱动海马神经元细胞死亡。

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摘要

The PSD-95 protein family organizes the glutamatergic postsynaptic density and it is involved in the regulation of the excitatory signal at central nervous system synapses. We show here that PSD-95 deficiency by means of antisense oligonucleotides induces significant neuronal cell death within 24 h both in primary hippocampal cultures and in organotypic hippocampal slices. On the other hand, cultured cortical neurons are spared by PSD-95 antisense toxicity until they reach a NR2A detectable protein level (24 days in vitro). The neurotoxic event is characterized by increased alpha CaMKII association to NR2 regulatory subunits of NMDA receptor complex. As a direct consequence of alpha CaMKII association, we found increased GluR1 delivery to cell surface in cultured hippocampal neurons paralleled by AMPA-dependent increase in [Na+]I levels. In addition, both CaMKII specific inhibitor KN-93 and AMPA receptor antagonists CNQX and NBQX rescued neuronal survival to control values. On the other hand, both the NMDA channel blocker MK-801 and Dantrolene, an inhibitor of calcium release from ryanodine-sensitive endoplasmic reticulum stores, failed to have any effect on neuronal survival in PSD-95 deficient neurons. Thus, our data provide clues that PSD-95 reduced expression in neurons is responsible for neuronal vulnerability mediated by direct activation of alpha CaMKII transduction pathway in the postsynaptic compartment.
机译：PSD-95蛋白家族可组织谷氨酸能突触后的密度，并参与中枢神经系统突触中兴奋性信号的调节。我们在这里显示，通过反义寡核苷酸的PSD-95缺乏诱导主要海马文化和器官型海马切片中的24小时内重大神经元细胞死亡。另一方面，培养的皮质神经元不受PSD-95反义毒性的影响，直到达到NR2A可检测的蛋白质水平（体外24天）。神经毒性事件的特征在于增加的αCaMKII与NMDA受体复合物的NR2调节亚基的缔合。作为αCaMKII关联的直接结果，我们发现培养的海马神经元中向细胞表面的GluR1传递增加，而AMPA依赖的[Na +] I水平增加。此外，CaMKII特异性抑制剂KN-93和AMPA受体拮抗剂CNQX和NBQX均可将神经元存活率恢复至控制值。另一方面，NMDA通道阻滞剂MK-801和Dantrolene，一种从瑞丹碱敏感性内质网存储中释放钙的抑制剂，均未对PSD-95缺陷神经元的神经元存活产生任何影响。因此，我们的数据提供了线索，提示PSD-95在神经元中的表达减少是由突触后区室中的αCaMKII转导途径的直接激活介导的神经元脆弱性的原因。

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