The calcium-regulated phosphodiesterase 1 (PDE1) family is highly expressed in the brain, but its functional role in neurones is poorly understood. Using the selective PDE1 inhibitor Lu AF64196 and biosensors for cyclic nucleotides including a novel biosensor for cGMP, we analyzed the effect of PDE1 on cAMP and cGMP in individual neurones in brain slices from male newborn mice. Release of caged NMDA triggered a transient increase of intracellular calcium, which was associated with a decrease in cAMP and cGMP in medium spiny neurones in the striatum. Lu AF64196 alone did not increase neuronal cyclic nucleotide levels, but blocked the NMDA-induced reduction in cyclic nucleotides indicating that this was mediated by calcium-activated PDE1. Similar effects were observed in the prefrontal cortex and the hippocampus. Upon corelease of dopamine and NMDA, PDE1 was shown to down-regulate the D1-receptor mediated increase in cAMP. PDE1 inhibition increased long-term potentiation in rat ventral striatum, showing that PDE1 is implicated in the regulation of synaptic plasticity. Overall, our results show that PDE1 reduces cyclic nucleotide signaling in the context of glutamate and dopamine coincidence. This effect could have a therapeutic value for treating brain disorders related to dysfunctions in dopamine neuromodulation.

中文翻译：

---

磷酸二酯酶1通过纹状体中的NO和多巴胺诱导的环状核苷酸信号桥接谷氨酸输入。

钙调节的磷酸二酯酶1（PDE1）家族在大脑中高度表达，但其在神经元中的功能作用却鲜为人知。使用选择性PDE1抑制剂Lu AF64196和用于环状核苷酸的生物传感器（包括用于cGMP的新型生物传感器），我们分析了PDE1对雄性新生小鼠脑切片中单个神经元中cAMP和cGMP的影响。释放笼中的NMDA会触发细胞内钙的瞬时增加，这与纹状体中棘状神经元中cAMP和cGMP的降低有关。单独的Lu AF64196不会增加神经元环状核苷酸的水平，但阻止了NMDA诱导的环状核苷酸的减少，表明这是由钙激活的PDE1介导的。在前额叶皮层和海马体中也观察到了类似的效果。多巴胺和NMDA共同释放后，已显示PDE1下调cAMP中D1受体介导的增加。PDE1抑制增加了大鼠腹侧纹状体的长期增强作用，表明PDE1与突触可塑性的调节有关。总体而言，我们的结果表明，PDE1在谷氨酸和多巴胺重合的情况下减少了环状核苷酸的信号传导。该作用对于治疗与多巴胺神经调节功能障碍有关的脑部疾病可能具有治疗价值。