Department of Pharmacology, Emory University School of Medicine, Atlanta, GA 30322, USA.
Proc Natl Acad Sci U S A. 2010 Sep 28;107(39):16994-8. doi: 10.1073/pnas.1005362107. Epub 2010 Sep 13.
Learning and memory have been closely linked to strengthening of synaptic connections between neurons (i.e., synaptic plasticity) within the dentate gyrus (DG)-CA3-CA1 trisynaptic circuit of the hippocampus. Conspicuously absent from this circuit is area CA2, an intervening hippocampal region that is poorly understood. Schaffer collateral synapses on CA2 neurons are distinct from those on other hippocampal neurons in that they exhibit a perplexing lack of synaptic long-term potentiation (LTP). Here we demonstrate that the signaling protein RGS14 is highly enriched in CA2 pyramidal neurons and plays a role in suppression of both synaptic plasticity at these synapses and hippocampal-based learning and memory. RGS14 is a scaffolding protein that integrates G protein and H-Ras/ERK/MAP kinase signaling pathways, thereby making it well positioned to suppress plasticity in CA2 neurons. Supporting this idea, deletion of exons 2-7 of the RGS14 gene yields mice that lack RGS14 (RGS14-KO) and now express robust LTP at glutamatergic synapses in CA2 neurons with no impact on synaptic plasticity in CA1 neurons. Treatment of RGS14-deficient CA2 neurons with a specific MEK inhibitor blocked this LTP, suggesting a role for ERK/MAP kinase signaling pathways in this process. When tested behaviorally, RGS14-KO mice exhibited marked enhancement in spatial learning and in object recognition memory compared with their wild-type littermates, but showed no differences in their performance on tests of nonhippocampal-dependent behaviors. These results demonstrate that RGS14 is a key regulator of signaling pathways linking synaptic plasticity in CA2 pyramidal neurons to hippocampal-based learning and memory but distinct from the canonical DG-CA3-CA1 circuit.
学习和记忆与海马体齿状回（DG）-CA3-CA1 三突触回路中神经元之间的突触连接增强（即突触可塑性）密切相关。这个回路中明显缺少 CA2 区，这是一个 intervening hippocampal region，人们对其知之甚少。CA2 神经元上的 Schaffer 侧枝突触与其他海马体神经元上的突触不同，因为它们表现出令人费解的缺乏突触长时程增强（LTP）。在这里，我们证明信号蛋白 RGS14 在 CA2 锥体神经元中高度富集，并在抑制这些突触的突触可塑性以及海马体相关的学习和记忆中发挥作用。RGS14 是一种支架蛋白，可整合 G 蛋白和 H-Ras/ERK/MAP 激酶信号通路，从而使其能够很好地抑制 CA2 神经元的可塑性。支持这一观点，RGS14 基因的外显子 2-7 缺失产生了缺乏 RGS14 的小鼠（RGS14-KO），现在 CA2 神经元中的谷氨酸能突触表现出强烈的 LTP，而对 CA1 神经元中的突触可塑性没有影响。用特异性 MEK 抑制剂处理缺乏 RGS14 的 CA2 神经元可阻断这种 LTP，表明 ERK/MAP 激酶信号通路在此过程中起作用。在行为测试中，与野生型同窝仔相比，RGS14-KO 小鼠在空间学习和物体识别记忆方面表现出明显增强，但在非海马依赖行为测试中的表现没有差异。这些结果表明，RGS14 是调节信号通路的关键调节因子，将 CA2 锥体神经元中的突触可塑性与海马体相关的学习和记忆联系起来，但与经典的 DG-CA3-CA1 回路不同。
