Stress Impairs Prefrontal Cortical Function via D1 Dopamine Receptor Interactions With Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels.
Stress Impairs Prefrontal Cortical Function via D1 Dopamine Receptor Interactions With Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels.
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DOI：
10.1016/j.biopsych.2015.01.009
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发表时间：
2015-12-15
影响因子：
10.6
通讯作者：
Arnsten AF
中科院分区：
文献类型：
--
作者：
Gamo NJ;Lur G;Higley MJ;Wang M;Paspalas CD;Vijayraghavan S;Yang Y;Ramos BP;Peng K;Kata A;Boven L;Lin F;Roman L;Lee D;Arnsten AF
精神分裂症等精神障碍会因压力而恶化，而工作记忆缺陷往往是疾病的主要特征。工作记忆是由前额叶皮质(PFC)锥体神经元的持续放电调节的。应激通过高水平的多巴胺D1受体(D1R)激活cAMP信号，从而减少PFC神经元的放电，从而损害工作记忆。目前的研究考察了D1R-cAMP信号是否通过增加超极化激活的环核苷酸门控(HCN)阳离子通道的开放状态来减少神经元的放电和损害工作记忆，这些阳离子通道集中在PFC锥体神经元相互连接的树突棘上。我们使用了多种方法来验证这一假设：双重免疫电子显微镜定位了D1R和HCN通道，体外记录测试了D1R对HCN通道电流(Ih)的作用，而执行工作记忆任务的猴子的记录测试了D1R-HCN通道的相互作用。最后，在PFC内注入药物后的认知评估检查了D1R-HCN通道交互作用对工作记忆表现的影响。免疫电子显微镜证实，在灵长类PFC的树突上，D1R与HCN通道位于兴奋性突触附近。小鼠PFC脑片记录显示，刺激D1R增加了ih，而局部阻断灵长类PFC的HCN通道则保护了D1R介导的任务相关放电的抑制。刺激大鼠或猴子PFC中的D1R可损害工作记忆成绩，而阻断PFC中的HCN通道可阻止应激或D1R刺激下的这种损害。这些发现表明，D1R刺激或应激通过开放网络突触上的HCN通道而削弱PFC功能。
Psychiatric disorders such as schizophrenia are worsened by stress, and working memory deficits are often a central feature of illness. Working memory is mediated by the persistent firing of prefrontal cortical (PFC) pyramidal neurons. Stress impairs working memory via high levels of dopamine D1 receptor (D1R) activation of cAMP signaling, which reduces PFC neuronal firing. The current study examined whether D1R-cAMP signaling reduces neuronal firing and impairs working memory by increasing the open state of hyperpolarization-activated cyclic nucleotide-gated (HCN) cation channels, which are concentrated on dendritic spines where PFC pyramidal neurons interconnect. A variety of methods were employed to test this hypothesis: dual immunoelectron microscopy localized D1R and HCN channels, in vitro recordings tested for D1R actions on HCN channel current (Ih), while recordings in monkeys performing a working memory task tested for D1R-HCN channel interactions in vivo. Finally, cognitive assessments following intra-PFC infusions of drugs examined D1R-HCN channel interactions on working memory performance. Immunoelectron microscopy confirmed D1R colocalization with HCN channels near excitatory-like synapses on dendritic spines in primate PFC. Mouse PFC slice recordings demonstrated that D1R stimulation increased Ih, while local HCN channel blockade in primate PFC protected task-related firing from D1R-mediated suppression. D1R stimulation in rat or monkey PFC impaired working memory performance, while HCN channel blockade in PFC prevented this impairment in rats exposed to either stress or D1R stimulation. These findings suggest that D1R stimulation or stress weakens PFC function via opening of HCN channels at network synapses.