Department of Physiology, Yokohama City University Graduate School of Medicine, Kanazawa-ku, Yokohama, Japan.
Proc Natl Acad Sci U S A. 2011 Jul 26;108(30):12503-8. doi: 10.1073/pnas.1104558108. Epub 2011 Jul 11.
The hippocampus plays a central role in learning and memory. Although synaptic delivery of AMPA-type glutamate receptors (AMPARs) contributes to experience-dependent synaptic strengthening, its role in hippocampus-dependent learning remains elusive. By combining viral-mediated in vivo gene delivery with in vitro patch-clamp recordings, we found that the inhibitory avoidance task, a hippocampus-dependent contextual fear-learning paradigm, delivered GluR1-containing AMPARs into CA3-CA1 synapses of the dorsal hippocampus. To block the synaptic delivery of endogenous AMPARs, we expressed a fragment of the GluR1-cytoplasmic tail (the 14-aa GluR1 membrane-proximal region with two serines mutated to phospho-mimicking aspartates: MPR-DD). MPR-DD prevented learning-driven synaptic AMPAR delivery in CA1 neurons. Bilateral expression of MPR-DD in the CA1 region of the rat impaired inhibitory avoidance learning, indicating that synaptic GluR1 trafficking in the CA1 region of the hippocampus is required for encoding contextual fear memories. The fraction of CA1 neurons that underwent synaptic strengthening positively correlated with the performance in the inhibitory avoidance fear memory task. These data suggest that the robustness of a contextual memory depends on the number of hippocampal neurons that participate in the encoding of a memory trace.
海马体在学习和记忆中起着核心作用。尽管 AMPA 型谷氨酸受体 (AMPARs) 的突触传递有助于依赖经验的突触增强，但它在海马体依赖学习中的作用仍不清楚。通过结合病毒介导的体内基因传递和体外膜片钳记录，我们发现，抑制回避任务，一种海马体依赖的情境性恐惧学习范式，将含有 GluR1 的 AMPAR 递送至海马体背侧 CA3-CA1 突触。为了阻断内源性 AMPAR 的突触传递，我们表达了 GluR1 胞质尾的一个片段（GluR1 膜近端区的 14 个氨基酸，其中两个丝氨酸突变为磷酸模拟天冬氨酸：MPR-DD）。MPR-DD 阻止了学习驱动的 CA1 神经元中的突触 AMPAR 传递。在大鼠海马体 CA1 区双侧表达 MPR-DD 会损害抑制性回避学习，表明海马体 CA1 区的突触 GluR1 转运对于编码情境性恐惧记忆是必需的。经历突触增强的 CA1 神经元的分数与抑制性回避恐惧记忆任务的表现呈正相关。这些数据表明，一个情境记忆的稳健性取决于参与记忆痕迹编码的海马体神经元的数量。
