Broad issues associated with non-replicability have been described in experimental pharmacological and behavioral cognitive studies. Efforts to prevent biases that contribute to non-replicable scientific protocols and to improve experimental rigor for reproducibility are increasingly seen as a basic requirement for the integrity of scientific research. Synaptic plasticity, encompassing long-term potentiation (LTP), is believed to underlie mechanisms of learning and memory. The present study was undertaken in Long-Evans (LE) rats, a strain of rat commonly used in cognitive behavioral tests, to (1) compare three LTP tetanisation protocols, namely, the high-frequency stimulation (HFS), the theta-burst stimulation (TBS), and the paired-pulse facilitation (PPF) at the Schaffer collateral-CA1 stratum radiatum synapse and to (2) assess sensitivity to acute pharmacology. Results: (1) When compared to Sprague-Dawley (SD) rats, the HFS using a stimulus intensity of 50% of the maximum slope obtained from input/output (I/O) curves elicited lower and higher thresholds of synaptic plasticity responses in SD and LE rats, respectively. The 2-train TBS protocol significantly enhanced the LTP response in LE rats over the 5- and 10-train TBS protocols in both strains, and the protocol inducing a subthreshold LTP response was used in subsequent pharmacological studies in LE rats. The PPF protocol, investigating the locus of the LTP response, showed no difference for the selected interstimulus intervals. (2) Scopolamine, a nonspecific muscarinic antagonist, had a subtle effect, whereas donepezil, an acetylcholinesterase inhibitor, significantly enhanced the LTP response, demonstrating the sensitivity of the TBS protocol to enhanced cholinergic tone. MK-801, a noncompetitive N-methyl-D-aspartate (NMDA) antagonist, significantly reduced LTP response, while memantine, another NMDA antagonist, had no effect on LTP response, likely associated with a weaker TBS protocol. PQ10, a phosphodiesterase-10 inhibitor, significantly enhanced the TBS-induced LTP response, but did not change the PPF response. Overall, the results confirm the strain-dependent differences in the form of synaptic plasticity, replicate earlier plasticity results, and report effective protocols that generate a relatively subthreshold margin of LTP induction and maintenance, which are suitable for pharmacology in the LE rat strain mainly used in cognitive studies.

中文翻译：

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海马 Schaffer 侧支 CA1 突触的体内可塑性：Long-Evans 大鼠中 LTP 反应和药理学的可重复性


实验药理学和行为认知研究中已经描述了与不可重复性相关的广泛问题。努力防止导致不可复制的科学方案的偏差以及提高实验严谨性以实现可重复性，越来越被视为科学研究完整性的基本要求。突触可塑性，包括长时程增强（LTP），被认为是学习和记忆机制的基础。本研究在 Long-Evans (LE) 大鼠（一种常用于认知行为测试的大鼠品系）中进行，目的是 (1) 比较三种 LTP 强直刺激方案，即高频刺激 (HFS)、theta 爆发刺激 (TBS) 和 Schaffer 侧支 CA1 放射层突触处的配对脉冲促进 (PPF) 以及 (2) 评估对急性药理学的敏感性。结果：(1) 与 Sprague-Dawley (SD) 大鼠相比，使用从输入/输出 (I/O) 曲线获得的最大斜率 50% 的刺激强度的 HFS 引起了较低和较高的突触可塑性反应阈值。分别为 SD 和 LE 大鼠。与 5 组和 10 组 TBS 方案相比，2 组 TBS 方案显着增强了 LE 大鼠的 LTP 反应，并且诱导阈下 LTP 反应的方案用于 LE 大鼠的后续药理学研究。 PPF 协议研究了 LTP 反应的轨迹，结果显示所选刺激间间隔没有差异。 (2) 东莨菪碱（一种非特异性毒蕈碱拮抗剂）具有微妙的作用，而多奈哌齐（一种乙酰胆碱酯酶抑制剂）则显着增强 LTP 反应，证明了 TBS 方案对增强胆碱能张力的敏感性。 MK-801 是一种非竞争性 N-甲基-D-天冬氨酸 (NMDA) 拮抗剂，可显着降低 LTP 反应，而另一种 NMDA 拮抗剂美金刚对 LTP 反应没有影响，可能与较弱的 TBS 方案有关。 PQ10 是一种磷酸二酯酶 10 抑制剂，可显着增强 TBS 诱导的 LTP 反应，但不会改变 PPF 反应。总体而言，结果证实了突触可塑性形式的品系依赖性差异，复制了早期的可塑性结果，并报告了产生 LTP 诱导和维持相对阈下边缘的有效方案，这些方案适用于主要使用的 LE 大鼠品系的药理学在认知研究中。