Serotonin induces Arcadlin in hippocampal neurons
Serotonin induces Arcadlin in hippocampal neurons
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DOI：
10.1016/j.neulet.2020.134783
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发表时间：
2020-01
影响因子：
2.5
通讯作者：
Hidekazu Tanaka;Toshinori Sawano;Naoko Konishi;Risako Harada;Chiaki Takeuchi;Yuki Shin;H. Sugiura;Jin Nakatani;T. Fujimoto;K. Yamagata
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文献类型：
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作者：
Hidekazu Tanaka;Toshinori Sawano;Naoko Konishi;Risako Harada;Chiaki Takeuchi;Yuki Shin;H. Sugiura;Jin Nakatani;T. Fujimoto;K. Yamagata
单胺假说不能完全解释抗抑郁药治疗后延迟恢复或电休克治疗后恢复的机制。在ECT和单胺能治疗中起作用的共同机制可能涉及在这两种情况下诱导的分子。棘密度调节剂Arcadlin（Acad）是人原钙粘蛋白-8（PCDH 8）和Xenopus和斑马鱼近轴原钙粘蛋白（PAPC）的大鼠直向同源物，其可由电惊厥发作（ECS）和抗抑郁药诱导;然而，其细胞机制仍然不清楚。在这里，我们证实诱导Arcadlin后，刺激培养的海马神经元中的N-甲基-D-天冬氨酸（NMDA）受体。NMDA受体的刺激也诱导p38丝裂原活化蛋白（MAP）激酶的急性（20分钟）和延迟（2小时）磷酸化，延迟磷酸化在Acad-/-神经元中不明显，表明它依赖于Arcadlin诱导。将高度成熟的培养海马神经元暴露于1-10 μM 5-羟色胺4 h导致Arcadlin诱导和p38 MAP激酶磷酸化。联合应用NMDA受体拮抗剂d-（-）-2-氨基-5-磷酸戊酸（APV）可完全阻断Arcadlin诱导和p38 MAP激酶磷酸化。最后，给予小鼠抗抑郁药氟西汀16天诱导海马中的Arcadlin表达。我们的数据表明，Arcadlin-p38 MAP激酶途径是一个候选的神经网络调制器，激活海马神经元的双重调节下的5-羟色胺和谷氨酸，因此，可能发挥作用，在抗抑郁治疗。
The monoamine hypothesis does not fully explain the delayed onset of recovery after antidepressant treatment or the mechanisms of recovery after electroconvulsive therapy (ECT). The common mechanism that operates both in ECT and monoaminergic treatment presumably involves molecules induced in both of these conditions. A spine density modulator, Arcadlin (Acad), the rat orthologue of human Protocadherin-8 (PCDH8) and ofXenopusand zebrafish Paraxial protocadherin (PAPC), is induced by both electroconvulsive seizure (ECS) and antidepressants; however, its cellular mechanism remains elusive. Here we confirm induction of Arcadlin upon stimulation of anN-methyl-d-aspartate (NMDA) receptor in cultured hippocampal neurons. Stimulation of an NMDA receptor also induced acute (20 min) and delayed (2 h) phosphorylation of the p38 mitogen-activated protein (MAP) kinase; the delayed phosphorylation was not obvious inAcad–/–neurons, suggesting that it depends on Arcadlin induction. Exposure of highly mature cultured hippocampal neurons to 1–10 μM serotonin for 4 h resulted in Arcadlin induction and p38 MAP kinase phosphorylation. Co-application of the NMDA receptor antagonistd-(-)-2-amino-5-phosphonopentanoic acid (APV) completely blocked Arcadlin induction and p38 MAP kinase phosphorylation. Finally, administration of antidepressant fluoxetine in mice for 16 days induced Arcadlin expression in the hippocampus. Our data indicate that the Arcadlin-p38 MAP kinase pathway is a candidate neural network modulator that is activated in hippocampal neurons under the dual regulation of serotonin and glutamate and, hence, may play a role in antidepressant therapies.