Repeated Blockade of NMDA Receptors During Adolescence Impairs Reversal Learning and Disrupts GABAergic Interneurons in Rat Medial Prefrontal Cortex.
Repeated Blockade of NMDA Receptors During Adolescence Impairs Reversal Learning and Disrupts GABAergic Interneurons in Rat Medial Prefrontal Cortex.
复制标题
青春期反复阻断 NMDA 受体会损害逆转学习并扰乱大鼠内侧前额叶皮质中的 GABA 能中间神经元
DOI：
10.3389/fnmol.2016.00017
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发表时间：
2016
影响因子：
4.8
通讯作者：
Si TM
中科院分区：
文献类型：
--
作者：
Li JT;Su YA;Wang HL;Zhao YY;Liao XM;Wang XD;Si TM
青春期对精神分裂症特别重要，因为精神病通常发生在这一关键时期。本研究基于精神分裂症的N-甲基-D-天冬氨酸(NMDA)受体功能低下假说，探讨青春期反复阻断NMDA受体是否以及如何影响大鼠内侧前额叶皮质(MPFC)GABA能中间神经元及其介导的认知功能。青春期大鼠给予非竞争性NMDA受体拮抗剂MK-801(0.1、0.2、0.4 mg/kg)连续14天，然后在水迷宫中测试参考记忆和反向学习。分别于停药后24 h和7 d检测mPFC内少量钙结合蛋白(PV)、钙结合蛋白(CB)和钙结合蛋白(CR)阳性神经元的密度。我们发现，MK-801处理延迟了水迷宫中的反转学习，而不影响初始获得。MK-801还显著降低了PV+和CB+神经元的密度，且在0.2 mg/kg剂量下停药后这种作用持续到第7天。我们进一步证明，PV+和CB+神经元密度的降低归因于PV和CB表达水平的下调，而不是神经元死亡。这些结果与精神分裂症的行为和神经病理变化相平行，并为青少年NMDA受体拮抗提供了一种有用的工具来解开疾病的病因。
Adolescence is of particular significance to schizophrenia, since psychosis onset typically occurs in this critical period. Based on the N-methyl-D-aspartate (NMDA) receptor hypofunction hypothesis of schizophrenia, in this study, we investigated whether and how repeated NMDA receptor blockade during adolescence would affect GABAergic interneurons in rat medial prefrontal cortex (mPFC) and mPFC-mediated cognitive functions. Specifically, adolescent rats were subjected to intraperitoneal administration of MK-801 (0.1, 0.2, 0.4 mg/kg), a non-competitive NMDA receptor antagonist, for 14 days and then tested for reference memory and reversal learning in the water maze. The density of parvabumin (PV)-, calbindin (CB)- and calretinin (CR)-positive neurons in mPFC was analyzed at either 24 h or 7 days after drug cessation. We found that MK-801 treatment delayed reversal learning in the water maze without affecting initial acquisition. Strikingly, MK-801 treatment also significantly reduced the density of PV+ and CB+ neurons, and this effect persisted for 7 days after drug cessation at the dose of 0.2 mg/kg. We further demonstrated that the reduction in PV+ and CB+ neuron densities was ascribed to a downregulation of the expression levels of PV and CB, but not to neuronal death. These results parallel the behavioral and neuropathological changes of schizophrenia and provide evidence that adolescent NMDA receptors antagonism offers a useful tool for unraveling the etiology of the disease.