Inhibition of protein kinase C signaling protects prefrontal cortex dendritic spines and cognition from the effects of chronic stress
Inhibition of protein kinase C signaling protects prefrontal cortex dendritic spines and cognition from the effects of chronic stress
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DOI：
10.1073/pnas.0908563106
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发表时间：
2009-10-20
影响因子：
11.1
通讯作者：
Arnsten, Amy F. T.
中科院分区：
文献类型：
--
作者：
Hains, Avis Brennan;Vu, Mai Anh T.;Arnsten, Amy F. T.
前额皮质通过工作记忆调节行为、认知和情绪。压力暴露会损害前额叶功能。急性应激诱导的缺陷是由过度的蛋白激酶C （PKC）信号引起的，它减少了前额叶神经元的放电。慢性应激还会产生结构变化，降低皮质-皮质锥体神经元的树突复杂性和脊柱密度，从而破坏兴奋性工作记忆网络。体外研究发现，持续的PKC活动导致海马培养神经元的脊柱丢失，这表明PKC可能在慢性应激暴露期间导致脊柱丢失。本研究测试了车车草碱在日常应激前抑制PKC是否能保护前额叶棘和工作记忆。我们发现PKC的抑制可以挽救工作记忆障碍，逆转大鼠边缘皮层第II/III层锥体神经元的远端根尖树突棘丢失。更大的脊柱密度预示着更好的认知能力，这是锥体细胞结构和工作记忆能力之间的第一个直接联系。这些发现表明PKC抑制剂可能对PKC信号失调的疾病有神经保护作用，如双相情感障碍、精神分裂症、创伤后应激障碍和铅中毒——这些疾病以前额叶结构和功能完整性差为特征。
The prefrontal cortex r regulates behavior, cognition, and emotion by using working memory. Prefrontal functions are impaired by stress exposure. Acute, stress-induced deficits arise from excessive protein kinase C (PKC) signaling, which diminishes prefrontal neuronal firing. Chronic stress additionally produces architectural changes, reducing dendritic complexity and spine density of cortico-cortical pyramidal neurons, thereby disrupting excitatory working memory networks. In vitro studies have found that sustained PKC activity leads to spine loss from hippocampal-cultured neurons, suggesting that PKC may contribute to spine loss during chronic stress exposure. The present study tested whether inhibition of PKC with chelerythrine before daily stress would protect prefrontal spines and working memory. We found that inhibition of PKC rescued working memory impairments and reversed distal apical dendritic spine loss in layer II/III pyramidal neurons of rat prelimbic cortex. Greater spine density predicted better cognitive performance, the first direct correlation between pyramidal cell structure and working memory abilities. These findings suggest that PKC inhibitors may be neuroprotective in disorders with dysregulated PKC signaling such as bipolar disorder, schizophrenia, post-traumatic stress disorder, and lead poisoning-conditions characterized by impoverished prefrontal structural and functional integrity.