Impaired spatial memory and enhanced long-term potentiation in mice with forebrain-specific ablation of the Stim genes.
Impaired spatial memory and enhanced long-term potentiation in mice with forebrain-specific ablation of the Stim genes.
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DOI：
10.3389/fnbeh.2015.00180
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发表时间：
2015
影响因子：
3
通讯作者：
Fivaz M
中科院分区：
文献类型：
--
作者：
Garcia-Alvarez G;Shetty MS;Lu B;Yap KA;Oh-Hora M;Sajikumar S;Bichler Z;Fivaz M
最近的研究结果指出，内质网驻留STIM（基质相互作用分子）蛋白在塑造哺乳动物大脑兴奋性突触的结构和功能中发挥着核心作用。然而，Stim基因对认知功能的影响仍然知之甚少。为了探索Stim基因在学习和记忆中的功能，我们在前脑中产生了三种具有条件性缺失（cKO）Stim 1和/或Stim 2的小鼠品系。Stim 1、Stim 2和双Stim 1/Stim 2 cKO小鼠未显示明显的脑结构缺陷或运动障碍。Morris水迷宫中的空间参考记忆分析显示，Stim 1 cKO小鼠存在轻度学习延迟，而Stim 2 cKO小鼠的学习和记忆与其对照同窝小鼠没有区别。然而，在前脑中缺失两种Stim基因导致空间学习和记忆的明显损害，反映了Stim基因对潜在神经回路的协同作用。值得注意的是，在Stim 1/Stim 2 cKO小鼠中，CA 3-CA 1海马突触的长时程增强（LTP）显著增强，并且与AMPA受体亚基GluA 1、转录调节因子CREB和蛋白激酶A（PKA）位点上的L型电压依赖性Ca 2+通道Cav1.2的磷酸化增加相关。我们的结论是，STIM 1和STIM 2的PKA信号和突触可塑性的神经回路编码空间记忆的关键调节器。我们的研究结果还揭示了LTP和空间学习/记忆之间的负相关性，并表明cAMP/PKA信号和突触效能的异常增强会破坏新记忆的形成。
Recent findings point to a central role of the endoplasmic reticulum-resident STIM (Stromal Interaction Molecule) proteins in shaping the structure and function of excitatory synapses in the mammalian brain. The impact of the Stim genes on cognitive functions remains, however, poorly understood. To explore the function of the Stim genes in learning and memory, we generated three mouse strains with conditional deletion (cKO) of Stim1 and/or Stim2 in the forebrain. Stim1, Stim2, and double Stim1/Stim2 cKO mice show no obvious brain structural defects or locomotor impairment. Analysis of spatial reference memory in the Morris water maze revealed a mild learning delay in Stim1 cKO mice, while learning and memory in Stim2 cKO mice was indistinguishable from their control littermates. Deletion of both Stim genes in the forebrain resulted, however, in a pronounced impairment in spatial learning and memory reflecting a synergistic effect of the Stim genes on the underlying neural circuits. Notably, long-term potentiation (LTP) at CA3-CA1 hippocampal synapses was markedly enhanced in Stim1/Stim2 cKO mice and was associated with increased phosphorylation of the AMPA receptor subunit GluA1, the transcriptional regulator CREB and the L-type Voltage-dependent Ca2+ channel Cav1.2 on protein kinase A (PKA) sites. We conclude that STIM1 and STIM2 are key regulators of PKA signaling and synaptic plasticity in neural circuits encoding spatial memory. Our findings also reveal an inverse correlation between LTP and spatial learning/memory and suggest that abnormal enhancement of cAMP/PKA signaling and synaptic efficacy disrupts the formation of new memories.