Groupe de Recherche sur le Système Nerveux Central (GRSNC) and Department of Physiology, Université de Montréal, Montreal, Quebec, Canada.
J Neurosci. 2012 May 2;32(18):6335-50. doi: 10.1523/JNEUROSCI.5463-11.2012.
Mounting evidence indicates an important role of long-term synaptic plasticity in hippocampal inhibitory interneurons in learning and memory. The cellular and molecular mechanisms that underlie such persistent changes in synaptic function in interneurons remain, however, largely undetermined. A transcription- and translation-dependent form of long-term potentiation was uncovered at excitatory synapses onto hippocampal interneurons in oriens-alveus (OA-INs) which is induced by activation of type 1 metabotropic glutamate receptors (cL-LTP(mGluR1)). Here, we use (1) a combination of pharmacological siRNA knock-down and overexpression approaches to reveal the molecular mechanisms of transcriptional control via cAMP response element-binding protein (CREB) during induction, and (2) quantal analysis to identify synaptic changes during maintenance of cL-LTP(mGluR1) in rat hippocampus. Induction stimulated CREB phosphorylation in OA-INs via extracellular signal-regulated protein kinase (ERK) signaling. Also, CREB knockdown impaired cL-LTP(mGluR1), whereas CREB overexpression facilitated the induction, demonstrating a necessary and permissive role of CREB via ERK signaling in transcriptional control in cL-LTP(mGluR1). Quantal analysis of synaptic responses during cL-LTP(mGluR1) maintenance revealed an increased number of quanta released, corresponding to enhanced transmitter release and a larger quantal size, indicating enhanced responsiveness to individual quanta. Fluctuation analysis of synaptic currents uncovered an increase in conductance and number of functional postsynaptic receptors contributing to single quanta. Our findings indicate that CREB-dependent transcription is a necessary permissive switch for eliciting persistent presynaptic and postsynaptic quantal changes at excitatory synapses in inhibitory local circuits, uncovering cell type-specific coupling of induction and expression mechanisms during persistent synaptic plasticity which may contribute to hippocampal long-term memory processes.
越来越多的证据表明，长时程突触可塑性在海马抑制性中间神经元的学习和记忆中起着重要作用。然而，这种中间神经元突触功能持续变化的细胞和分子机制在很大程度上仍未确定。在海马齿状回内分子层（OA-INs）的兴奋性突触上发现了一种依赖于转录和翻译的长时程增强形式，这种增强是由 1 型代谢型谷氨酸受体（mGluR1）的激活所诱导的（cL-LTP(mGluR1)）。在这里，我们使用（1）药理学 siRNA 敲低和过表达方法的组合，揭示了诱导过程中通过 cAMP 反应元件结合蛋白（CREB）的转录控制的分子机制，以及（2）量子分析，以确定大鼠海马体中 cL-LTP(mGluR1)维持期间的突触变化。诱导通过细胞外信号调节蛋白激酶（ERK）信号刺激 OA-INs 中的 CREB 磷酸化。此外，CREB 敲低削弱了 cL-LTP(mGluR1)，而 CREB 过表达促进了诱导，证明了 CREB 通过 ERK 信号在 cL-LTP(mGluR1)的转录控制中的必要和许可作用。在 cL-LTP(mGluR1)维持期间的突触反应量子分析显示，释放的量子数量增加，对应于递质释放的增强和量子大小的增大，表明对单个量子的反应性增强。突触电流的波动分析揭示了单个量子贡献的电导和功能性突触后受体数量的增加。我们的发现表明，CREB 依赖性转录是在抑制性局部回路中的兴奋性突触上引发持续的突触前和突触后量子变化的必要许可开关，揭示了在持续的突触可塑性过程中诱导和表达机制的细胞类型特异性耦合，这可能有助于海马体的长期记忆过程。
