Serine Racemase and D-serine in the Amygdala Are Dynamically Involved in Fear Learning.
Serine Racemase and D-serine in the Amygdala Are Dynamically Involved in Fear Learning.
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DOI：
10.1016/j.biopsych.2017.08.012
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发表时间：
2018-02-01
影响因子：
10.6
通讯作者：
Coyle JT
中科院分区：
文献类型：
--
作者：
Balu DT;Presti KT;Huang CCY;Muszynski K;Radzishevsky I;Wolosker H;Guffanti G;Ressler KJ;Coyle JT
杏仁核是恐惧学习的神经回路的中心组成部分。杏仁核中依赖N-甲基-D-天冬氨酸受体(NMDAR)的可塑性是巴甫洛夫恐惧条件反射和消退所必需的。NMDAR的激活需要协同激动剂D-丝氨酸的结合，D-丝氨酸是由神经元酶丝氨酸消旋酶(SR)由L丝氨酸合成的。然而，人们对杏仁核中SR和D-丝氨酸的功能知之甚少。我们用免疫组织化学方法研究了SR和D-丝氨酸在小鼠和人类杏仁核中的细胞定位。利用生化和分子技术，我们确定了微量恐惧的条件反射和消退是否与大脑中的SR和D-丝氨酸有关。系统地给小鼠注射D-丝氨酸，评估其消除恐惧的效果。最后，我们调查了功能性SNP(Rs4523957)，它是人类丝氨酸消旋酶(SRR)基因的表达连锁数量性状基因座(EQTL)，是否与高度创伤的人类队列中的恐惧相关表型有关。我们证明了杏仁核中大约一半的神经元表达SR，包括兴奋性和抑制性神经元。我们发现，恐惧记忆的获得和消退涉及到小鼠杏仁核中的SR/D-丝氨酸系统，而D-丝氨酸的使用有助于恐惧的消退。我们还证明了SRR SNP rs4523957与人类创伤后应激障碍(PTSD)有关，这与D-丝氨酸促进恐惧消退的作用是一致的。这些新发现对理解D-丝氨酸介导的杏仁核NMDAR可塑性以及该系统如何促进具有不适应恐惧回路的障碍具有重要意义。
The amygdala is a central component of the neural circuitry that underlies fear learning. N-methyl-D-aspartate receptor (NMDAR)-dependent plasticity in the amygdala is required for Pavlovian fear conditioning and extinction. NMDAR activation requires the binding of a co-agonist, D-serine, which is synthesized from L-serine by the neuronal enzyme serine racemase (SR). However, little is known about SR and D-serine function in the amygdala. We used immunohistochemical methods to characterize the cellular localization of SR and D-serine in the mouse and human amygdala. Using biochemical and molecular techniques, we determined whether trace fear conditioning and extinction engages the SR and D-serine in the brain. D-serine was administered systemically to mice evaluate its effect on fear extinction. Finally, we investigated whether a functional SNP (rs4523957), which is an expression-linked quantitative trait locus (eQTL) of the human serine racemase (SRR) gene, was associated with fear-related phenotypes in a highly traumatized human cohort. We demonstrate that approximately half of the neurons in the amygdala express SR, including both excitatory and inhibitory neurons. We find that the acquisition and extinction of fear memory engages the SR/D-serine system in the mouse amygdala and that D-serine administration facilitates fear extinction. We also demonstrate that the SRR SNP, rs4523957, is associated with post-traumatic stress disorder (PTSD) in humans, consistent with the facilitatory effect of D-serine on fear extinction. These new findings have important implications for understanding D-serine mediated NMDAR plasticity in the amygdala and how this system could contribute to disorders with maladaptive fear circuitry.
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