Department of Physiology & Biophysics, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, 675 Hoes Lane West, Piscataway, NJ 08854, USA.
Neuropharmacology. 2012 Oct;63(5):837-41. doi: 10.1016/j.neuropharm.2012.06.014. Epub 2012 Jun 18.
Previous work demonstrated that basal alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor activity did not contribute to the elevated regional cerebral O₂ consumption in the brains of Eker rat (an autism-tuberous sclerosis model). We tested the hypothesis that increased stimulation of AMPA receptors also would not augment cerebral O₂ consumption in the Eker rat. Three cortical sites were prepared for administration of saline, 10⁻⁴ and 10⁻³ M AMPA in young (4 weeks) male control Long Evans and Eker rats (70-100 g). Cerebral blood flow (¹⁴C-iodoantipyrine) and O₂ consumption (cryomicrospectrophotometry) were determined in isoflurane anesthetized rats. Receptor levels were studied through Western analysis of the GLuR1 subunit of the AMPA receptor. We found significantly increased cortical O₂ consumption (+33%) after 10⁻⁴ M AMPA in control rats. The higher dose of AMPA did not further increase consumption. In the Eker rats, neither dose led to a significant increase in cortical O₂ consumption. Regional blood flow followed a similar pattern to oxygen consumption but cortical O₂ extraction did not differ. Cortical AMPA receptor protein levels were significantly reduced (-21%) in the Eker compared to control rats. Both O₂ consumption and blood flow were significantly elevated in the pons of the Eker rats compared to control. These data demonstrate a reduced importance of AMPA receptors in the control of cortical metabolism, related to reduced AMPA receptor protein, in the Eker rat. This suggests that increasing AMPA receptor activity may not be an effective treatment for children with autism spectrum disorders as they also have reduced AMPA receptor number.
先前的工作表明，基底α-氨基-3-羟基-5-甲基-4-异恶唑丙酸（AMPA）受体活性不会导致 Eker 大鼠（自闭症-结节性硬化症模型）大脑中局部脑氧消耗增加。我们测试了这样一个假设，即 AMPA 受体的过度刺激也不会增加 Eker 大鼠的脑氧消耗。在年轻（4 周）雄性对照长爪沙鼠和 Eker 大鼠的三个皮质部位准备给予生理盐水、10⁻⁴和 10⁻³ M AMPA。在异氟醚麻醉大鼠中测定脑血流（¹⁴C-碘安替比林）和氧消耗（低温微量分光光度法）。通过 Western 分析 AMPA 受体的 GLuR1 亚基研究受体水平。我们发现，在对照大鼠中，10⁻⁴ M AMPA 后皮质氧消耗显著增加（增加 33%）。更高剂量的 AMPA 并没有进一步增加消耗。在 Eker 大鼠中，两种剂量均未导致皮质氧消耗显著增加。局部血流遵循与氧消耗相似的模式，但皮质氧提取没有差异。与对照大鼠相比，Eker 大鼠皮质 AMPA 受体蛋白水平显著降低（降低 21%）。与对照大鼠相比，Eker 大鼠脑桥的氧消耗和血流均显著升高。这些数据表明，在 Eker 大鼠中，由于 AMPA 受体蛋白减少，AMPA 受体在皮质代谢控制中的重要性降低。这表明增加 AMPA 受体活性可能不是自闭症谱系障碍儿童的有效治疗方法，因为他们的 AMPA 受体数量也减少了。
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