Department of Physiology, Faculty of Medicine, University of Toronto, 1 King's College Circle, Toronto, Ontario, Canada.
Mol Brain. 2010 Jan 21;3:3. doi: 10.1186/1756-6606-3-3.
The downstream regulatory element antagonist modulator (DREAM), a multifunctional Ca2+-binding protein, binds specifically to DNA and several nucleoproteins regulating gene expression and with proteins outside the nucleus to regulate membrane excitability or calcium homeostasis. DREAM is highly expressed in the central nervous system including the hippocampus and cortex; however, the roles of DREAM in hippocampal synaptic transmission and plasticity have not been investigated. Taking advantage of transgenic mice overexpressing a Ca2+-insensitive DREAM mutant (TgDREAM), we used integrative methods including electrophysiology, biochemistry, immunostaining, and behavior tests to study the function of DREAM in synaptic transmission, long-term plasticity and fear memory in hippocampal CA1 region. We found that NMDA receptor but not AMPA receptor-mediated current was decreased in TgDREAM mice. Moreover, synaptic plasticity, such as long-term depression (LTD) but not long-term potentiation (LTP), was impaired in TgDREAM mice. Biochemical experiments found that DREAM interacts with PSD-95 and may inhibit NMDA receptor function through this interaction. Contextual fear memory was significantly impaired in TgDREAM mice. By contrast, sensory responses to noxious stimuli were not affected. Our results demonstrate that DREAM plays a novel role in postsynaptic modulation of the NMDA receptor, and contributes to synaptic plasticity and behavioral memory.
下游调节元件拮抗剂调制器 (DREAM) 是一种多功能 Ca2+结合蛋白，特异性地与 DNA 和几种核蛋白结合，调节基因表达，并与核外的蛋白质结合，调节膜兴奋性或钙稳态。DREAM 在中枢神经系统中高度表达，包括海马体和皮质;然而，DREAM 在海马体突触传递和可塑性中的作用尚未被研究。利用过表达一种 Ca2+不敏感的 DREAM 突变体 (TgDREAM) 的转基因小鼠，我们使用包括电生理学、生物化学、免疫染色和行为测试在内的综合方法，研究了 DREAM 在海马体 CA1 区突触传递、长期可塑性和恐惧记忆中的功能。我们发现，在 TgDREAM 小鼠中，NMDA 受体介导的电流而不是 AMPA 受体介导的电流减少。此外，在 TgDREAM 小鼠中，突触可塑性，如长时程压抑 (LTD) 而不是长时程增强 (LTP)，受损。生化实验发现，DREAM 与 PSD-95 相互作用，并可能通过这种相互作用抑制 NMDA 受体功能。在 TgDREAM 小鼠中，情境性恐惧记忆明显受损。相比之下，对有害刺激的感觉反应不受影响。我们的结果表明，DREAM 在 NMDA 受体的突触后调节中发挥新的作用，并有助于突触可塑性和行为记忆。
