Mikics Eva, Toth Mate, Biro Laszlo, Bruzsik Biborka, Nagy Boglarka, Haller Jozsef
Institute of Experimental Medicine, Department of Behavioral Neuroscience, P.O. Box 67, H-1450 Budapest, Hungary.
Institute of Experimental Medicine, Department of Behavioral Neuroscience, P.O. Box 67, H-1450 Budapest, Hungary.
Physiol Behav. 2017 Aug 1;177:44-48. doi: 10.1016/j.physbeh.2017.04.005. Epub 2017 Apr 8.
N-methyl-d-aspartate (NMDA) receptors are crucial synaptic elements in long-term memory formation, including the associative learning of fearful events. Although NMDA blockers were consistently shown to inhibit fear memory acquisition and recall, the clinical use of general NMDA blockers is hampered by their side effects. Recent studies revealed significant heterogeneity in the distribution and neurophysiological characteristics of NMDA receptors with different GluN2 (NR2) subunit composition, which may have differential role in fear learning and recall. To investigate the specific role of NMDA receptor subpopulations with different GluN2 subunit compositions in the formation of lasting traumatic memories, we contrasted the effects of general NMDA receptor blockade with GluN2A-, GluN2B-, and GluN2C/D subunit selective antagonists (MK-801, PEAQX, Ro25-6981, PPDA, respectively). To investigate acute and lasting consequences, behavioral responses were investigated 1 and 28days after fear conditioning. We found that MK-801 (0.05 and 0.1mg/kg) decreased fear recall at both time points. GluN2B receptor subunit blockade produced highly similar effects, albeit efficacy was somewhat smaller 28days after fear conditioning. Unlike MK-801, Ro25-6981 (3 and 10mg/kg) did not affect locomotor activity in the open-field. In contrast, GluN2A and GluN2C/D blockers (6 and 20mg/kg PEAQX; 3 and 10mg/kg PPDA, respectively) had no effect on conditioned fear recall at any time point and dose. This sharp contrast between GluN2B- and other subunit-containing NMDA receptor function indicates that GluN2B receptor subunits are intimately involved in fear memory formation, and may provide a novel pharmacological target in post-traumatic stress disorder or other fear-related disorders.
N-甲基-D-天冬氨酸（NMDA）受体是长期记忆形成过程中的关键突触元件，包括恐惧事件的关联性学习。尽管NMDA受体阻滞剂一直被证明可抑制恐惧记忆的获取和回忆，但一般NMDA受体阻滞剂的临床应用因其副作用而受到阻碍。最近的研究揭示了具有不同GluN2（NR2）亚基组成的NMDA受体在分布和神经生理学特征上存在显著异质性，这可能在恐惧学习和回忆中具有不同作用。为了研究具有不同GluN2亚基组成的NMDA受体亚群在持久创伤性记忆形成中的具体作用，我们对比了一般NMDA受体阻滞剂与GluN2A、GluN2B和GluN2C/D亚基选择性拮抗剂（分别为MK-801、PEAQX、Ro25-6981、PPDA）的效果。为了研究急性和持久后果，在恐惧条件反射后1天和28天对行为反应进行了研究。我们发现，MK-801（0.05和0.1mg/kg）在两个时间点均降低了恐惧回忆。GluN2B受体亚基阻滞剂产生了高度相似的效果，尽管在恐惧条件反射后28天其效力略小。与MK-801不同，Ro25-6981（3和10mg/kg）不影响旷场中的运动活动。相反，GluN2A和GluN2C/D阻滞剂（分别为6和20mg/kg PEAQX；3和10mg/kg PPDA）在任何时间点和剂量下对条件性恐惧回忆均无影响。GluN2B与其他含亚基的NMDA受体功能之间的这种鲜明对比表明，GluN2B受体亚基密切参与恐惧记忆形成，并且可能为创伤后应激障碍或其他恐惧相关疾病提供新的药理学靶点。
