Promoter-Specific Effects of DREADD Modulation on Hippocampal Synaptic Plasticity and Memory Formation
Promoter-Specific Effects of DREADD Modulation on Hippocampal Synaptic Plasticity and Memory Formation
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DOI：
10.1523/jneurosci.3682-15.2016
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发表时间：
2016-03-23
影响因子：
5.3
通讯作者：
Wood, Marcelo A.
中科院分区：
文献类型：
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作者：
Lopez, Alberto J.;Kramar, Enikoe;Wood, Marcelo A.
由设计药物(DREADDS)独有激活的设计受体是一种新的工具，具有双向驱动细胞、电路和最终行为改变的潜力。我们使用DREADDS来评估小鼠在海马体依赖任务中的记忆形成以及对背侧海马区突触生理学的影响。我们在背侧海马区表达神经元特异性(hSyn启动子)DREADD，这些DREADD既是兴奋性的(HM3D)，也是抑制性的(HM4D)。正如预测的那样，hSyn-HM3D能够将亚阈值学习事件转化为长时记忆(LTM)，而hSyn-HM4D完全损害了LTM的形成。令人惊讶的是，在测试对海马长时程增强(LTP)的影响的实验中，观察到了相反的情况。HSyn-HM3D损伤LTP，hSyn-HM4D促进LTP。后续实验表明，hSyn-HM3D介导的fEPSP的抑制可能是由突触前抑制电流的激活所驱动的，而hSyn-HM4D介导的fEPSP的增加则是由GABA(A)受体功能的降低引起的。为了确定这些观察是否具有启动子特异性，我们接下来检查了使用CaMKIIα启动子将表达限制在前脑兴奋性神经元的效果。在背侧海马区，CaMKIIα-HM3D导致了阈值下学习事件向LTM的转变，而CaMKIIα-HM4D阻止了LTM的形成。与这些发现一致的是，CaMKIIα-HM3D海马片的基线突触传递和LTP增加，而CaMKIIα-HM4D小鼠的脑片预期基线突触传递和LTP减少。综上所述，这些实验进一步证明，DREADDS是一种强大而可靠的手段，可以调节神经元功能，以操纵行为的长期变化，同时为LTM和LTP之间的特定分离提供证据。
Designer receptors exclusively activated by designer drug (DREADDs) are a novel tool with the potential to bidirectionally drive cellular, circuit, and ultimately, behavioral changes. We used DREADDs to evaluate memory formation in a hippocampus-dependent task in mice and effects on synaptic physiology in the dorsal hippocampus. We expressed neuron-specific (hSyn promoter) DREADDs that were either excitatory (HM3D) or inhibitory (HM4D) in the dorsal hippocampus. As predicted, hSyn-HM3D was able to transform a subthreshold learning event into long-term memory (LTM), and hSyn-HM4D completely impaired LTM formation. Surprisingly, the opposite was observed during experiments examining the effects on hippocampal long-term potentiation (LTP). hSyn-HM3D impaired LTP and hSyn-HM4D facilitated LTP. Follow-up experiments indicated that the hSyn-HM3D-mediated depression of fEPSP appears to be driven by presynaptic activation of inhibitory currents, whereas the hSyn-HM4D-mediated increase of fEPSP is induced by a reduction in GABA(A) receptor function. To determine whether these observations were promoter specific, we next examined the effects of using the CaMKII alpha promoter that limits expression to forebrain excitatory neurons. CaMKII alpha-HM3D in the dorsal hippocampus led to the transformation of a subthreshold learning event into LTM, whereas CaMKII alpha-HM4D blocked LTM formation. Consistent with these findings, baseline synaptic transmission and LTP was increased in CaMKII alpha-HM3D hippocampal slices, whereas slices from CaMKII alpha-HM4D mice produced expected decreases in baseline synaptic transmission and LTP. Together, these experiments further demonstrate DREADDs as being a robust and reliable means of modulating neuronal function to manipulate long-term changes in behavior, while providing evidence for specific dissociations between LTM and LTP.