Shahoha Meishar, Cohen Ronni, Ben-Simon Yoav, Ashery Uri
Faculty of Life Sciences, School of Neurobiology, Biochemistry and Biophysics, Tel Aviv University, Tel Aviv, Israel.
Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel.
Front Synaptic Neurosci. 2022 Apr 4;14:861215. doi: 10.3389/fnsyn.2022.861215. eCollection 2022.
Cyclic adenosine monophosphate (cAMP) is a crucial second messenger involved in both pre- and postsynaptic plasticity in many neuronal types across species. In the hippocampal mossy fiber (MF) synapse, cAMP mediates presynaptic long-term potentiation and depression. The main cAMP-dependent signaling pathway linked to MF synaptic plasticity acts via the activation of the protein kinase A (PKA) molecular cascade. Accordingly, various downstream putative synaptic PKA target proteins have been linked to cAMP-dependent MF synaptic plasticity, such as synapsin, rabphilin, synaptotagmin-12, RIM1a, tomosyn, and P/Q-type calcium channels. Regulating the expression of some of these proteins alters synaptic release probability and calcium channel clustering, resulting in short- and long-term changes to synaptic efficacy. However, despite decades of research, the exact molecular mechanisms by which cAMP and PKA exert their influences in MF terminals remain largely unknown. Here, we review current knowledge of different cAMP catalysts and potential downstream PKA-dependent molecular cascades, in addition to non-canonical cAMP-dependent but PKA-independent cascades, which might serve as alternative, compensatory or competing pathways to the canonical PKA cascade. Since several other central synapses share a similar form of presynaptic plasticity with the MF, a better description of the molecular mechanisms governing MF plasticity could be key to understanding the relationship between the transcriptional and computational levels across brain regions.
环磷酸腺苷（cAMP）是一种关键的第二信使，参与了跨物种的多种神经元类型的突触前和突触后可塑性。在海马苔藓纤维（MF）突触中，cAMP介导突触前长期增强和抑制。与MF突触可塑性相关的主要cAMP依赖性信号通路通过蛋白激酶A（PKA）分子级联的激活起作用。因此，各种下游假定的突触PKA靶蛋白已与cAMP依赖性MF突触可塑性相关联，例如突触素、rabphilin、突触结合蛋白-12、RIM1a、tomosyn和P/Q型钙通道。调节其中一些蛋白的表达会改变突触释放概率和钙通道聚集，从而导致突触效能的短期和长期变化。然而，尽管经过了数十年的研究，cAMP和PKA在MF终末发挥作用的确切分子机制在很大程度上仍然未知。在这里，我们回顾了关于不同cAMP催化剂和潜在的下游PKA依赖性分子级联的当前知识，以及非经典的cAMP依赖性但PKA非依赖性级联，它们可能作为经典PKA级联的替代、补偿或竞争途径。由于其他几个中枢突触与MF具有相似形式的突触前可塑性，更好地描述控制MF可塑性的分子机制可能是理解跨脑区转录水平和计算水平之间关系的关键。
