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首页> 美国卫生研究院文献>The Journal of Neuroscience >NMDA Receptor Antagonists Disinhibit Rat Posterior Cingulate and Retrosplenial Cortices: A Potential Mechanism of Neurotoxicity
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NMDA Receptor Antagonists Disinhibit Rat Posterior Cingulate and Retrosplenial Cortices: A Potential Mechanism of Neurotoxicity

机译：NMDA受体拮抗剂抑制大鼠后扣带和脾后皮质：神经毒性的潜在机制。

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NMDA receptor antagonists produce region-specific neurodegeneration by an undetermined mechanism, but one proposed mechanism involves disinhibition. In certain areas of the brain, NMDA receptors mediate excitatory drive onto inhibitory interneurons. Thus, NMDA receptor/channel antagonists may reduce inhibition (i.e., produce “disinhibition”). If a sufficient level of disinhibition is produced, enhanced vulnerability to excitotoxicity may result. Furthermore, if there are region-specific differences in NMDA antagonist-induced disinhibition, this could underlie region-specific NMDA antagonist-induced neurotoxicity. In the present study, we tested this hypothesis by exposing rat brain slices to the NMDA receptor antagonist dizocilpine maleate (MK-801) and measuring MK-801-induced disinhibition in areas of higher and lower vulnerability to neurodegeneration [posterior cingulate/retrosplenial cortices (PCC/RSC) and parietal cortex, respectively]. Using whole-cell patch-clamp techniques, bicuculline-sensitive GABAAreceptor-mediated IPSCs were measured in biocytin-labeled pyramidal neurons in the PCC/RSC and parietal cortex. In the PCC/RSC, bath-applied MK-801 (10–40 μm) produced disinhibition, shown as a concentration-dependent decrease in spontaneous IPSC frequency and amplitude; MK-801 (40 μm) also reduced evoked IPSC amplitudes. In parietal cortex, MK-801 produced significantly less disinhibition. To determine whether disinhibition is caused by presynaptic or postsynaptic mechanisms, we tested the effects of MK-801 (40 μm) against miniature IPSC (mIPSC) frequency and amplitude in tetrodotoxin (TTX; 0.5 μm)-treated slices and found that MK-801 did not alter mIPSC frequency or amplitude. Taken together, these results suggest that NMDA receptors regulate activity of inhibitory interneurons and, consequently, GABA release in certain cortical areas. This region-specific reduction in inhibitory input to pyramidal cells could underlie the region-specific neurotoxicity of NMDA antagonists.
机译：NMDA受体拮抗剂通过不确定的机制产生区域特异性神经变性，但一种拟议的机制涉及去抑制作用。在大脑的某些区域，NMDA受体介导兴奋性驱动到抑制性中间神经元上。因此，NMDA受体/通道拮抗剂可以降低抑制作用（即产生“去抑制作用”）。如果产生足够水平的去抑制作用，则可能导致兴奋性毒性增强。此外，如果NMDA拮抗剂诱导的去抑制作用存在区域特异性差异，则这可能是区域特异性NMDA拮抗剂诱导的神经毒性的基础。在本研究中，我们通过将大鼠脑片暴露于NMDA受体拮抗剂马来酸双唑西平（MK-801）并在对神经变性较高和较低的脆弱性区域[后扣带/后脾皮质（ PCC / RSC）和顶叶皮层]。使用全细胞膜片钳技术，在PCC / RSC和顶叶皮层中生物素标记的锥体神经元中测量了双小分子敏感的GABAA受体介导的IPSC。在PCC / RSC中，浸浴的MK-801（10–40μm）产生了抑制作用，表现为自发IPSC频率和振幅的浓度依赖性降低； MK-801（40μm）也降低了诱发的IPSC振幅。在顶叶皮层中，MK-801产生的去抑制作用明显减少。为了确定去抑制作用是由突触前还是突触后机制引起的，我们测试了MK-801（40μm）对河豚毒素（TTX; 0.5μm）处理过的切片中微型IPSC（mIPSC）频率和振幅的影响，并发现MK-801并没有改变mIPSC的频率或幅度。综上所述，这些结果表明，NMDA受体调节抑制性中间神经元的活性，并因此调节某些皮质区域的GABA释放。锥体细胞抑制性输入的这种区域特异性减少可能是NMDA拮抗剂的区域特异性神经毒性的基础。

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