The second messenger cAMP is an important determinant of synaptic plasticity that is associated with enhanced neurotransmitter release. Long-term potentiation (LTP) at parallel fiber (PF)–Purkinje cell (PC) synapses depends on a Ca²⁺-induced increase in presynaptic cAMP that is mediated by Ca²⁺-sensitive adenylyl cyclases. However, the upstream signaling and the downstream targets of cAMP involved in these events remain poorly understood. It is unclear whether cAMP generated by β-adrenergic receptors (βARs) is required for PF–PC LTP, although noradrenergic varicosities are apposed in PF–PC contacts. Guanine nucleotide exchange proteins directly activated by cAMP [Epac proteins (Epac 1-2)] are alternative cAMP targets to protein kinase A (PKA) and Epac2 is abundant in the cerebellum. However, whether Epac proteins participate in PF–PC LTP is not known. Immunoelectron microscopy demonstrated that βARs are expressed in PF boutons. Moreover, activation of these receptors through their agonist isoproterenol potentiated synaptic transmission in cerebellar slices from mice of either sex, an effect that was insensitive to the PKA inhibitors (H-89, KT270) but that was blocked by the Epac inhibitor ESI 05. Interestingly, prior activation of these βARs occluded PF–PC LTP, while the β1AR antagonist metoprolol blocked PF–PC LTP, which was also absent in Epac2^–/– mice. PF–PC LTP is associated with an increase in the size of the readily releasable pool (RRP) of synaptic vesicles, consistent with the isoproterenol-induced increase in vesicle docking in cerebellar slices. Thus, the βAR-mediated modulation of the release machinery and the subsequent increase in the size of the RRP contributes to PF–PC LTP.

SIGNIFICANCE STATEMENT G-protein-coupled receptors modulate the release machinery, causing long-lasting changes in synaptic transmission that influence synaptic plasticity. Nevertheless, the mechanisms underlying synaptic responses to β-adrenergic receptor (βAR) activation remain poorly understood. An increase in the number of synaptic vesicles primed for exocytosis accounts for the potentiation of neurotransmitter release driven by βARs. This effect is not mediated by the canonical protein kinase A pathway but rather, through direct activation of the guanine nucleotide exchange protein Epac by cAMP. Interestingly, this βAR signaling via Epac is involved in long term potentiation at cerebellar granule cell-to-Purkinje cell synapses. Thus, the pharmacological activation of βARs modulates synaptic plasticity and opens therapeutic opportunities to control this phenomenon.

第二信使cAMP是与增强的神经递质释放相关的突触可塑性的重要决定因素。平行纤维（PF）–Purkinje细胞（PC）突触的长期增强（LTP）取决于Ca ²⁺诱导的由Ca ²⁺介导的突触前cAMP的增加敏感的腺苷酸环化酶。但是，仍然不清楚这些事件中涉及的cAMP的上游信号和下游靶标。PF-PC LTP是否需要由β-肾上腺素能受体（βARs）产生的cAMP，尽管PF-PC接触中存在去甲肾上腺素的静脉曲张。由cAMP直接激活的鸟嘌呤核苷酸交换蛋白[Epac蛋白（Epac 1-2）]是蛋白激酶A（PKA）的替代cAMP靶标，Epac2在小脑中含量很高。但是，尚不知道Epac蛋白是否参与PF-PC LTP。免疫电子显微镜证实，βARs在PF钮扣中表达。而且，通过受体激动剂异丙肾上腺素对这些受体的激活增强了来自任何性别小鼠的小脑切片中的突触传递，Epac2 ^{– / –}小鼠。PF–PC LTP与突触小泡容易释放池（RRP）的大小增加相关，这与异丙肾上腺素引起的小脑薄片小泡对接的增加一致。因此，βAR介导的释放机制的调节和随后RRP尺寸的增加有助于PF-PC LTP。

重要性声明G蛋白偶联受体调节释放机制，导致突触传递的持久变化，影响突触可塑性。然而，对β-肾上腺素受体（βAR）激活的突触反应的潜在机制仍知之甚少。引发胞吐的突触小泡数量增加，说明了βARs驱动的神经递质释放增强。这种作用不是由经典的蛋白激酶A途径介导的，而是由cAMP直接激活鸟嘌呤核苷酸交换蛋白Epac介导的。有趣的是，经由Epac的βAR信号转导参与了小脑颗粒细胞与普金野细胞突触的长期增强。因此，βARs的药理学激活可调节突触可塑性，并为控制这种现象提供治疗机会。