RGS14 is a natural suppressor of both synaptic plasticity in CA2 neurons and hippocampal-based learning and memory
RGS14 is a natural suppressor of both synaptic plasticity in CA2 neurons and hippocampal-based learning and memory
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DOI：
10.1073/pnas.1005362107
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发表时间：
2010-09-28
影响因子：
11.1
通讯作者：
Hepler, John R.
中科院分区：
文献类型：
--
作者：
Lee, Sarah Emerson;Simons, Stephen B.;Hepler, John R.
学习和记忆与海马齿状回 (DG)-CA3-CA1 三突触回路内神经元之间突触连接的加强（即突触可塑性）密切相关。该环路中明显缺少 CA2 区，这是一个人们知之甚少的中间海马区。 CA2 神经元上的 Schaffer 侧支突触与其他海马神经元上的侧支突触不同，因为它们表现出突触长时程增强 (LTP) 的令人困惑的缺乏。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和基于海马的学习和记忆中发挥作用。 RGS14 是一种支架蛋白，整合了 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。支持这一观点的是，删除 RGS14 基因的外显子 2-7 会产生缺乏 RGS14 (RGS14-KO) 的小鼠，并且现在在 CA2 神经元的谷氨酸突触处表达强大的 LTP，而对 CA1 神经元的突触可塑性没有影响。用特定的 MEK 抑制剂治疗 RGS14 缺陷的 CA2 神经元可阻断该 LTP，表明 ERK/MAP 激酶信号通路在此过程中发挥作用。在行为测试中，与野生型同窝小鼠相比，RGS14-KO 小鼠在空间学习和物体识别记忆方面表现出显着增强，但在非海马依赖性行为测试中表现出无差异。这些结果表明，RGS14 是将 CA2 锥体神经元突触可塑性与海马学习和记忆联系起来的信号通路的关键调节因子，但与典型的 DG-CA3-CA1 回路不同。
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.