NR2C 敲除小鼠的行为分析显示其在条件性恐惧获得和工作记忆方面存在缺陷。
Behavioral analysis of NR2C knockout mouse reveals deficit in acquisition of conditioned fear and working memory.
机构信息
Department of Pharmacology, Creighton University, Omaha, NE 68178, USA.
出版信息
Neurobiol Learn Mem. 2011 May;95(4):404-14. doi: 10.1016/j.nlm.2011.01.008. Epub 2011 Feb 2.
Abstract
N-methyl-D-aspartate (NMDA) receptors play an important role in excitatory neurotransmission and mediate synaptic plasticity associated with learning and memory. NMDA receptors are composed of two NR1 and two NR2 subunits and the identity of the NR2 subunit confers unique electrophysiologic and pharmacologic properties to the receptor. The precise role of NR2C-containing receptors in vivo is poorly understood. We have performed a battery of behavioral tests on NR2C knockout/nβ-galactosidase knock-in mice and found no difference in spontaneous activity, basal anxiety, forced-swim immobility, novel object recognition, pain sensitivity and reference memory in comparison to wildtype counterparts. However, NR2C knockout mice were found to exhibit deficits in fear acquisition and working memory compared to wildtype mice. Deficit in fear acquisition correlated with lack of fear conditioning-induced plasticity at the thalamo-amygdala synapse. These findings suggest a unique role of NR2C-containing receptors in associative and executive learning representing a novel therapeutic target for deficits in cognition.
摘要
N-甲基-D-天冬氨酸（NMDA）受体在兴奋性神经递质传递中发挥重要作用，并介导与学习和记忆相关的突触可塑性。NMDA 受体由两个 NR1 和两个 NR2 亚基组成，NR2 亚基的身份赋予受体独特的电生理和药理学特性。NR2C 包含的受体在体内的确切作用知之甚少。我们对 NR2C 敲除/β-半乳糖苷酶敲入小鼠进行了一系列行为测试，与野生型相比，在自发活动、基础焦虑、强迫游泳不动、新物体识别、疼痛敏感性和参考记忆方面没有差异。然而，与野生型小鼠相比，NR2C 敲除小鼠在恐惧获得和工作记忆方面表现出缺陷。恐惧获得的缺陷与丘脑-杏仁核突触处缺乏恐惧条件反射诱导的可塑性相关。这些发现表明 NR2C 包含的受体在联想和执行学习中具有独特的作用，代表认知缺陷的一个新的治疗靶点。
相似文献
1
Behavioral analysis of NR2C knockout mouse reveals deficit in acquisition of conditioned fear and working memory.NR2C 敲除小鼠的行为分析显示其在条件性恐惧获得和工作记忆方面存在缺陷。
Neurobiol Learn Mem. 2011 May;95(4):404-14. doi: 10.1016/j.nlm.2011.01.008. Epub 2011 Feb 2.
2
Concomitant deficits in working memory and fear extinction are functionally dissociated from reduced anxiety in metabotropic glutamate receptor 7-deficient mice.代谢型谷氨酸受体7缺陷小鼠中，工作记忆和恐惧消退的伴随性缺陷与焦虑减轻在功能上是分离的。
J Neurosci. 2006 Jun 14;26(24):6573-82. doi: 10.1523/JNEUROSCI.1497-06.2006.
3
Gender specific requirement of GluR1 receptors in contextual conditioning but not spatial learning.谷氨酸受体 1 在情境条件反射中存在性别特异性需求，但在空间学习中则没有。
Neurobiol Learn Mem. 2011 Oct;96(3):461-7. doi: 10.1016/j.nlm.2011.07.001. Epub 2011 Jul 24.
4
Aquaporin-4 deficiency impairs synaptic plasticity and associative fear memory in the lateral amygdala: involvement of downregulation of glutamate transporter-1 expression.水通道蛋白-4 缺乏损害外侧杏仁核的突触可塑性和联想性恐惧记忆：涉及谷氨酸转运体-1 表达下调。
Neuropsychopharmacology. 2012 Jul;37(8):1867-78. doi: 10.1038/npp.2012.34. Epub 2012 Apr 4.
5
Synaptic transmission and plasticity in the amygdala. An emerging physiology of fear conditioning circuits.杏仁核中的突触传递与可塑性。恐惧条件反射回路的新兴生理学。
Mol Neurobiol. 1996 Aug;13(1):1-22. doi: 10.1007/BF02740749.
6
Homeostatic switch in hebbian plasticity and fear learning after sustained loss of Cav1.2 calcium channels.持续丧失 Cav1.2 钙通道后赫伯型可塑性和恐惧学习中的体内平衡开关。
J Neurosci. 2010 Jun 23;30(25):8367-75. doi: 10.1523/JNEUROSCI.4164-08.2010.
7
Deletion of glutamate delta-1 receptor in mouse leads to enhanced working memory and deficit in fear conditioning.谷氨酸 delta-1 受体缺失的小鼠表现出增强的工作记忆和恐惧条件反射缺陷。
PLoS One. 2013;8(4):e60785. doi: 10.1371/journal.pone.0060785. Epub 2013 Apr 3.
8
9
stathmin, a gene enriched in the amygdala, controls both learned and innate fear.Stathmin是一种在杏仁核中高度富集的基因，它控制着习得性恐惧和先天性恐惧。
Cell. 2005 Nov 18;123(4):697-709. doi: 10.1016/j.cell.2005.08.038.
10
Impaired spatial working memory but spared spatial reference memory following functional loss of NMDA receptors in the dentate gyrus.齿状回中NMDA受体功能丧失后，空间工作记忆受损，但空间参考记忆保留。
Eur J Neurosci. 2007 Feb;25(3):837-46. doi: 10.1111/j.1460-9568.2007.05312.x.
引用本文的文献
1
Dorsal raphe stimulation relays a reward signal to the ventral tegmental area via GluN2C NMDA receptors.背缝核刺激通过 GluN2C NMDA 受体将奖励信号传递到腹侧被盖区。
PLoS One. 2023 Nov 6;18(11):e0293564. doi: 10.1371/journal.pone.0293564. eCollection 2023.
2
Discovery of ()-2-amino-3-triazolpropanoic acid derivatives as NMDA receptor glycine site agonists with GluN2 subunit-specific activity.发现（）-2-氨基-3-三唑丙酸衍生物作为具有GluN2亚基特异性活性的NMDA受体甘氨酸位点激动剂。 （注：原文括号处内容缺失）
Front Chem. 2022 Nov 17;10:1008233. doi: 10.3389/fchem.2022.1008233. eCollection 2022.
3
Glutamate delta 1 receptor regulates autophagy mechanisms and affects excitatory synapse maturation in the somatosensory cortex.谷氨酸δ1受体调节自噬机制并影响体感皮层兴奋性突触的成熟。
Pharmacol Res. 2022 Apr;178:106144. doi: 10.1016/j.phrs.2022.106144. Epub 2022 Mar 15.
4
Roles of Phosphorylation of N-Methyl-D-Aspartate Receptor in Chronic Pain.N-甲基-D-天冬氨酸受体磷酸化在慢性疼痛中的作用
Cell Mol Neurobiol. 2023 Jan;43(1):155-175. doi: 10.1007/s10571-022-01188-6. Epub 2022 Jan 15.
5
Structure, Function, and Pharmacology of Glutamate Receptor Ion Channels.谷氨酸受体离子通道的结构、功能和药理学。
Pharmacol Rev. 2021 Oct;73(4):298-487. doi: 10.1124/pharmrev.120.000131.
6
Astrocyte GluN2C NMDA receptors control basal synaptic strengths of hippocampal CA1 pyramidal neurons in the .星形细胞 GluN2C NMDA 受体控制海马 CA1 锥体神经元的基础突触强度。
Elife. 2021 Oct 25;10:e70818. doi: 10.7554/eLife.70818.
7
Clinical and therapeutic significance of genetic variation in the GRIN gene family encoding NMDARs.GRIN 基因家族编码的 NMDAR 中遗传变异的临床和治疗意义。
Neuropharmacology. 2021 Nov 1;199:108805. doi: 10.1016/j.neuropharm.2021.108805. Epub 2021 Sep 22.
8
Astrocytic NMDA Receptors in the Basolateral Amygdala Contribute to Facilitation of Fear Extinction.外侧杏仁核中的星形细胞 NMDA 受体有助于促进恐惧的消除。
Int J Neuropsychopharmacol. 2021 Nov 12;24(11):907-919. doi: 10.1093/ijnp/pyab055.
9
GluN2D NMDA Receptors Gate Fear Extinction Learning and Interneuron Plasticity.谷氨酸N2D型N-甲基-D-天冬氨酸受体调控恐惧消退学习及中间神经元可塑性。
Front Synaptic Neurosci. 2021 May 24;13:681068. doi: 10.3389/fnsyn.2021.681068. eCollection 2021.
10
Involvement of NMDA receptors containing the GluN2C subunit in the psychotomimetic and antidepressant-like effects of ketamine.NMDA 受体中 GluN2C 亚基的参与介导了氯胺酮的致幻和抗抑郁样作用。
Transl Psychiatry. 2020 Dec 10;10(1):427. doi: 10.1038/s41398-020-01110-y.
本文引用的文献
1
Plastic synaptic networks of the amygdala for the acquisition, expression, and extinction of conditioned fear.杏仁核的可塑性突触网络，用于条件性恐惧的获得、表达和消除。
Physiol Rev. 2010 Apr;90(2):419-63. doi: 10.1152/physrev.00037.2009.
2
Structural determinants of D-cycloserine efficacy at the NR1/NR2C NMDA receptors.D-环丝氨酸在 NR1/NR2C NMDA 受体上的疗效的结构决定因素。
J Neurosci. 2010 Feb 17;30(7):2741-54. doi: 10.1523/JNEUROSCI.5390-09.2010.
3
Inhibition of NMDARs in the Nucleus Reticularis of the Thalamus Produces Delta Frequency Bursting.丘脑网状核中 NMDA 受体的抑制导致 δ 频率爆发。
Front Neural Circuits. 2009 Nov 10;3:20. doi: 10.3389/neuro.04.020.2009. eCollection 2009.
4
Gene expression of NMDA receptor subunits in the cerebellum of elderly patients with schizophrenia.老年精神分裂症患者小脑 NMDA 受体亚单位的基因表达。
Eur Arch Psychiatry Clin Neurosci. 2010 Mar;260(2):101-11. doi: 10.1007/s00406-009-0017-1. Epub 2009 May 12.
5
Hippocampal NMDA receptor subunits differentially regulate fear memory formation and neuronal signal propagation.海马体 NMDA 受体亚基对恐惧记忆形成和神经元信号传递有不同的调节作用。
Hippocampus. 2010 Sep;20(9):1072-82. doi: 10.1002/hipo.20705.
6
Alterations of excitatory transmission in the lateral amygdala during expression and extinction of fear memory.外侧杏仁核中兴奋性传递在恐惧记忆表达和消退期间的改变。
Int J Neuropsychopharmacol. 2010 Apr;13(3):335-45. doi: 10.1017/S1461145709990678. Epub 2009 Sep 24.
7
Cerebellum and emotional behavior.小脑与情绪行为。
Neuroscience. 2009 Sep 1;162(3):756-62. doi: 10.1016/j.neuroscience.2009.01.064. Epub 2009 Feb 3.
8
Synaptic AMPA receptor plasticity and behavior.突触AMPA受体可塑性与行为
Neuron. 2009 Feb 12;61(3):340-50. doi: 10.1016/j.neuron.2009.01.015.
9
Contribution of hippocampal and extra-hippocampal NR2B-containing NMDA receptors to performance on spatial learning tasks.海马体和海马体外含NR2B的N-甲基-D-天冬氨酸受体对空间学习任务表现的作用。
Neuron. 2008 Dec 10;60(5):846-60. doi: 10.1016/j.neuron.2008.09.039.
10
Activation of recombinant NR1/NR2C NMDA receptors.重组NR1/NR2C N-甲基-D-天冬氨酸受体的激活
J Physiol. 2008 Sep 15;586(18):4425-39. doi: 10.1113/jphysiol.2008.158634. Epub 2008 Jul 17.
Zotero 插件