Department of Physiology and Institute of Neuroscience and Mental Health, University of Alberta School of Medicine, Edmonton, Alberta T6G 2H7, Canada.
Learn Mem. 2019 Jan 16;26(2):31-38. doi: 10.1101/lm.048660.118. Print 2019 Feb.
Beta-adrenergic receptor (β-AR) activation by norepinephrine (NE) enhances memory and stabilizes long-term potentiation (LTP), a form of synaptic plasticity believed to underlie some forms of hippocampal memory. LTP can occur at multiple synaptic pathways as a result of strong stimulation to one pathway preceding milder stimulation of an adjacent, independent pathway. Synaptic tagging allows LTP to be transferred, or captured, at heterosynaptic pathways. Previous research has shown that β-AR activation promotes heterosynaptic LTP by engaging various signaling cascades. In particular, cyclic adenosine monophosphate (cAMP) activates cAMP-dependent protein kinase A (PKA) and guanine nucleotide exchange protein activated by cAMP (Epac), to enhance LTP. Epac activation can occlude subsequent induction of stable homosynaptic LTP after β-AR activation, but it is unclear whether Epac activation is required for heterosynaptic LTP following pairing of the natural transmitter, NE, with one 100 Hz train of stimulation ("NE-LTP"). Using electrophysiologic recordings of CA1 field excitatory postsynaptic potentials during stimulation of two independent synaptic pathways in murine hippocampal slices, we show that distinct inhibitors of Epac blocked stabilization of homo- and heterosynaptic NE-LTP. PKA inhibition also attenuated heterosynaptic transfer of NE-LTP, but only when a PKA inhibitor was applied during tetanization of a second, heterosynaptic pathway that was not treated with NE. Our data suggest that NE, paired with 100 Hz, activates Epac to stabilize homo- and heterosynaptic LTP. Epac may regulate the production of plasticity-related proteins and subsequent synaptic capture of NE-LTP at a heterosynaptic pathway. Epac activation under these conditions may enable behavioral experiences that engage noradrenergic inputs to hippocampal circuits to be transformed into stable long-term memories.
β-肾上腺素能受体 (β-AR) 被去甲肾上腺素 (NE) 激活后可增强记忆并稳定长时程增强 (LTP)，LTP 是一种被认为是海马体记忆的某些形式的基础的突触可塑性。由于对一条通路进行强烈刺激，随后对相邻的、独立的通路进行较弱刺激，LTP 可以在多条突触通路上发生。突触标记允许 LTP 在异突触通路上被转移或捕获。先前的研究表明，β-AR 激活通过参与各种信号级联反应来促进异突触 LTP。特别是，环腺苷酸 (cAMP) 激活 cAMP 依赖性蛋白激酶 A (PKA) 和 cAMP 激活的鸟苷酸交换蛋白 (Epac)，以增强 LTP。Epac 的激活可以阻断随后在β-AR 激活后稳定诱导同源突触 LTP，但尚不清楚 Epac 的激活是否是在与天然递质 NE 配对后诱导异突触 LTP 所必需的，NE 与 100 Hz 的刺激串 ("NE-LTP")。使用在小鼠海马切片中刺激两个独立的突触通路期间 CA1 场兴奋性突触后电位的电生理记录，我们表明 Epac 的不同抑制剂阻断了同源和异突触 NE-LTP 的稳定。PKA 抑制剂也减弱了异突触 NE-LTP 的转移，但仅当在第二个异突触通路上应用 PKA 抑制剂进行强直刺激时，该通路上未用 NE 处理。我们的数据表明，NE 与 100 Hz 配对激活 Epac 以稳定同源和异突触 LTP。Epac 可能调节可塑性相关蛋白的产生，并随后在异突触通路上捕获 NE-LTP。在这些条件下，Epac 的激活可能使参与海马体回路的去甲肾上腺素输入的行为体验转化为稳定的长期记忆。
