Clozapine functions through the prefrontal cortex serotonin 1A receptor to heighten neuronal activity via calmodulin kinase II-NMDA receptor interactions.
Clozapine functions through the prefrontal cortex serotonin 1A receptor to heighten neuronal activity via calmodulin kinase II-NMDA receptor interactions.
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DOI：
10.1111/j.1471-4159.2011.07565.x
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发表时间：
2012-02
影响因子：
4.7
通讯作者：
Banerjee P
中科院分区：
文献类型：
--
作者：
Purkayastha S;Ford J;Kanjilal B;Diallo S;Del Rosario Inigo J;Neuwirth L;El Idrissi A;Ahmed Z;Wieraszko A;Azmitia EC;Banerjee P
前额叶皮层（PFC）中多巴胺的异常释放被认为是精神分裂症的基础，但广泛使用的抗精神病药氯氮平（Clz）引起神经递质释放电刺激的机制途径尚不清楚。我们分析了Clz诱发的调节PFC中的神经元活动，刺激轴突在第IV和V层，并记录在突触后锥体细胞的第II和III层的电效应。我们观察到Clz诱发的群体峰电位（PS）增加，这是由5-羟色胺1A受体（5-HT 1A-R）、磷脂酶Cβ和Ca 2 +/钙调蛋白依赖性蛋白激酶II（CaMK II）介导的。免疫印迹表明，Clz激活的CaMK Ⅱ是5-HT 1A-R介导的。有趣的是，N-甲基-D-天冬氨酸受体（NMDA-R）拮抗剂（±）2-氨基-5-膦酰基戊酸（APV）消除了Clz介导的PS增加，表明5-HT 1A-R、NMDA-R和CaMK II形成协同三联体，其增强兴奋性突触后电位（EPSP），从而增强PS。在证实，Clz以及NMDA增强场EPSP（fEPSP），WAY 100635（5-HT 1A-R拮抗剂），APV，和CaMK Ⅱ抑制剂消除这种增加。如前所述，CaMKII与NMDA-R NR 2B亚基结合，变得具有组成性活性，从而诱导α-氨基-3-羟基-5-甲基-4-异恶唑丙酸酯（AMPA）受体募集至突触后膜，并增加fEPSP。免疫共沉淀表明，Clz可能在突触后密度的膜筏中增强CaMKII、NR 2B和5-HT 1A-R之间的相互作用，因为用甲基-β-环糊精（一种破坏筏的试剂）预处理抑制了免疫共沉淀和fEPSP。总之，氯氮平通过协调5-HT 1A-R、CaMKII和NMDA-R之间的协同作用在PFC中发挥作用，这增强了PFC第II/III层神经元的兴奋性。
Aberrant dopamine release in the prefrontal cortex (PFC) is believed to underlie schizophrenia, but the mechanistic pathway through which a widely used antipsychotic, clozapine (Clz), evokes neurotransmitter-releasing electrical stimulation is unclear. We analyzed Clz-evoked regulation of neuronal activity in the PFC by stimulating axons in layers IV and V and recording the electrical effect in the postsynaptic pyramidal cells of layers II and III. We observed a Clz-evoked increase in population spike (PS), which was mediated by serotonin 1A receptor (5-HT1A-R), phospholipase Cβ, and Ca2+/calmodulin-dependent protein kinase II (CaMKII). Immunoblotting demonstrated that the Clz-activation of CaMKII was 5-HT1A-R-mediated. Intriguingly, the N-methyl-D-aspartic acid receptor (NMDA-R) antagonist (±)2-Amino-5-phosphonovaleric acid (APV) eliminated the Clz-mediated increase in PS, suggesting that the 5-HT1A-R, NMDA-R and CaMKII form a synergistic triad, which boosts excitatory post-synaptic potential (EPSP), thereby enhancing PS. In corroboration, Clz as well as NMDA augmented field EPSP (fEPSP), and WAY100635 (a 5-HT1A-R antagonist), APV, and a CaMKII inhibitor eliminated this increase. As previously shown, CaMKII binds to the NMDA-R NR2B subunit to become constitutively active, thereby inducing α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA) receptor recruitment to the postsynaptic membrane and an increase in fEPSP. Coimmunoprecipitation demonstrated that Clz potentiates interactions among CaMKII, NR2B, and 5-HT1A-R, possibly in the membrane rafts of the postsynaptic density, because pretreatment with methyl-ß-cyclodextrin, an agent that disrupts rafts, inhibited both coimmunoprecipitation as well as fEPSP. In summary, clozapine functions in the PFC by orchestrating a synergism among 5-HT1A-R, CaMKII, and NMDA-R, which augments excitability in the PFC neurons of layers II/III.
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影响因子：
5.3
作者：
Díaz-Mataix, L;Scorza, MC;Artigas, F
通讯作者：
Artigas, F
影响因子：
3.4
作者：
Auclair, A;Drouin, C;Tassin, JP
通讯作者：
Tassin, JP
影响因子：
5
作者：
FORSTER, EA;CLIFFE, IA;FLETCHER, A
通讯作者：
FLETCHER, A
影响因子：
3.3
作者：
Broderick, PA;Piercey, MF
通讯作者：
Piercey, MF
影响因子：
2.5
作者：
KIM, JS;KORNHUBER, HH;HOLZMULLER, B
通讯作者：
HOLZMULLER, B