Loss of Tsc1 in vivo impairs hippocampal mGluR-LTD and increases excitatory synaptic function.
Loss of Tsc1 in vivo impairs hippocampal mGluR-LTD and increases excitatory synaptic function.
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DOI：
10.1523/jneurosci.1617-11.2011
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发表时间：
2011-06-15
期刊：
影响因子：
--
通讯作者：
Sabatini BL
中科院分区：
文献类型：
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作者：
Bateup HS;Takasaki KT;Saulnier JL;Denefrio CL;Sabatini BL
自闭症谱系障碍结节性硬化症 (TSC) 是由 Tsc1 或 Tsc2 基因突变引起的，这些基因的蛋白质产物形成异二聚体复合物，负向调节 mTOR 依赖性蛋白质翻译。尽管几种形式的突触可塑性，包括代谢型谷氨酸受体依赖性长期抑制 (mGluR-LTD)，依赖于诱导时的蛋白质翻译，但尚不清楚这些形式的可塑性是否需要通过 Tsc1/2 复合物进行信号传导。为了检验这种可能性，我们在小鼠体内通过病毒传递 Cre 重组酶，在体内删除了海马 CA1 神经元子集中的 Tsc1。我们发现海马 mGluR-LTD 因 Tsc1 的缺失而被消除，而 NMDA 受体依赖性 LTD 的不依赖于蛋白质合成的形式被保留。此外，Tsc1 KO 神经元中 AMPA 和 NMDA 受体介导的兴奋性突触后电流 (EPSC) 和微型自发 EPSC 频率也有所增强。突触功能的这些变化是在棘密度、形态或突触前释放概率没有改变的情况下发生的。我们的研究结果表明，通过 Tsc1/2 的信号传导是海马突触可塑性特定形式的表达以及正常兴奋性突触强度维持所必需的。此外，这些数据表明突触信号传导的扰动可能有助于 TSC 的发病机制。
The autism-spectrum disorder Tuberous Sclerosis Complex (TSC) is caused by mutations in the Tsc1 or Tsc2 genes whose protein products form a heterodimeric complex that negatively regulates mTOR-dependent protein translation. Although several forms of synaptic plasticity, including metabotropic glutamate receptor-dependent long-term depression (mGluR-LTD), depend on protein translation at the time of induction, it is unknown if these forms of plasticity require signaling through the Tsc1/2 complex. To examine this possibility, we postnatally deleted Tsc1 in vivo in a subset of hippocampal CA1 neurons using viral delivery of Cre recombinase in mice. We found that hippocampal mGluR-LTD was abolished by loss of Tsc1, whereas a protein synthesis-independent form of NMDA receptor-dependent LTD was preserved. Additionally, AMPA and NMDA receptor mediated excitatory postsynaptic currents (EPSCs) and miniature spontaneous EPSC frequency were enhanced in Tsc1 KO neurons. These changes in synaptic function occurred in the absence of alterations in spine density, morphology, or pre-synaptic release probability. Our findings indicate that signaling through Tsc1/2 is required for the expression of specific forms of hippocampal synaptic plasticity as well as the maintenance of normal excitatory synaptic strength. Furthermore, these data suggest that perturbations of synaptic signaling may contribute to the pathogenesis of TSC.