Tsinghua-Peking Center for Life Sciences, School of Medicine, Tsinghua University, 100084 Beijing, China.
J Neurosci. 2011 Oct 19;31(42):14871-81. doi: 10.1523/JNEUROSCI.3782-11.2011.
Anxiety disorders, such as phobias and posttraumatic stress disorder, are among the most common mental disorders. Cognitive therapy helps in treating these disorders; however, many cases relapse or resist the therapy, which justifies the search for cognitive enhancers that might augment the efficacy of cognitive therapy. Studies suggest that enhancement of plasticity in certain brain regions such as the prefrontal cortex (PFC) and/or hippocampus might enhance the efficacy of cognitive therapy. We found that elevation of brain magnesium, by a novel magnesium compound [magnesium-l-threonate (MgT)], enhances synaptic plasticity in the hippocampus and learning and memory in rats. Here, we show that MgT treatment enhances retention of the extinction of fear memory, without enhancing, impairing, or erasing the original fear memory. We then explored the molecular basis of the effects of MgT treatment on fear memory and extinction. In intact animals, elevation of brain magnesium increased NMDA receptors (NMDARs) signaling, BDNF expression, density of presynaptic puncta, and synaptic plasticity in the PFC but, interestingly, not in the basolateral amygdala. In vitro, elevation of extracellular magnesium concentration increased synaptic NMDAR current and plasticity in the infralimbic PFC, but not in the lateral amygdala, suggesting a difference in their sensitivity to elevation of brain magnesium. The current study suggests that elevation of brain magnesium might be a novel approach for enhancing synaptic plasticity in a regional-specific manner leading to enhancing the efficacy of extinction without enhancing or impairing fear memory formation.
焦虑症，如恐惧症和创伤后应激障碍，是最常见的精神障碍之一。认知疗法有助于治疗这些疾病；然而，许多病例会复发或抗拒治疗，这证明了寻找认知增强剂的合理性，这些增强剂可能会增强认知疗法的疗效。研究表明，增强前额叶皮层（PFC）和/或海马体等特定脑区的可塑性可能会增强认知疗法的疗效。我们发现，一种新型镁化合物[镁-L-苏糖酸（MgT）]可提高大脑镁含量，从而增强海马体的突触可塑性以及大鼠的学习和记忆能力。在这里，我们表明 MgT 处理可增强恐惧记忆消退的保留，而不会增强、损害或消除原始恐惧记忆。然后，我们探讨了 MgT 处理对恐惧记忆和消退的影响的分子基础。在完整动物中，大脑镁含量的升高增加了 NMDA 受体（NMDAR）信号、BDNF 表达、突触前突密度和 PFC 的突触可塑性，但有趣的是，在基底外侧杏仁核中没有增加。在体外，细胞外镁浓度的升高增加了内侧前额叶皮层（infralimbic PFC）的突触 NMDAR 电流和可塑性，但在外侧杏仁核中没有增加，这表明它们对大脑镁升高的敏感性存在差异。本研究表明，提高大脑镁含量可能是一种新的方法，可以以区域特异性的方式增强突触可塑性，从而增强消退的疗效，而不会增强或损害恐惧记忆的形成。
