Department of Neuroscience, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
Psychopharmacology (Berl). 2012 Jan;219(1):47-58. doi: 10.1007/s00213-011-2375-4. Epub 2011 Jun 10.
Studies in the Fmr1 knockout (KO) mouse, a model of fragile X syndrome (FXS), suggest that excessive signaling through group I metabotropic glutamate receptors (mGluRs), comprised of subtypes mGluR1 and mGluR5, may play a role in the pathogenesis of FXS. Currently, no studies have assessed the effect of mGluR1 modulation on Fmr1 KO behavior, and there has not been an extensive behavioral analysis of mGluR5 manipulation in Fmr1 KO mice.
The goals for this study were to determine if pharmacologic blockade of mGluR1 may affect Fmr1 KO behavior as well as to expand on the current literature regarding pharmacologic blockade of mGluR5 on Fmr1 KO behavior.
Reduction of mGluR1 or mGluR5 activity was evaluated on a variety of behavioral assays in wild-type (WT) and Fmr1 KO mice through the use of antagonists: JNJ16259685 (JNJ, mGluR1 antagonist) and MPEP (mGluR5 antagonist).
JNJ and MPEP decreased marble burying in both WT and Fmr1 KO mice without reductions in activity. Neither JNJ nor MPEP affected the prepulse inhibition in either WT or Fmr1 KO mice. JNJ did not affect Fmr1 KO motor coordination but did impair WT performance. MPEP improved a measure of motor learning in Fmr1 KO but not WT mice. While both JNJ and MPEP decreased the audiogenic seizures in the Fmr1 KO, MPEP completely abolished the manifestation of seizures.
These data illustrate that, while the manipulation of either mGluR1 or mGluR5 can affect select behaviors in the Fmr1 KO, we observe greater effects upon mGluR5 reduction.
脆性 X 综合征（FXS）模型 Fmr1 敲除（KO）小鼠的研究表明，I 组代谢型谷氨酸受体（mGluRs）过度信号传导，由 mGluR1 和 mGluR5 亚型组成，可能在 FXS 的发病机制中发挥作用。目前，尚无研究评估 mGluR1 调节对 Fmr1 KO 行为的影响，也没有对 Fmr1 KO 小鼠中 mGluR5 操作的广泛行为分析。
本研究的目的是确定 mGluR1 药理学阻断是否可能影响 Fmr1 KO 行为，并扩展关于 mGluR5 药理学阻断对 Fmr1 KO 行为的现有文献。
通过使用拮抗剂 JNJ16259685（JNJ，mGluR1 拮抗剂）和 MPEP（mGluR5 拮抗剂），在野生型（WT）和 Fmr1 KO 小鼠的各种行为测定中评估 mGluR1 或 mGluR5 活性的降低。
JNJ 和 MPEP 降低了 WT 和 Fmr1 KO 小鼠的大理石掩埋，但没有降低活动。JNJ 和 MPEP 均未影响 WT 或 Fmr1 KO 小鼠的前脉冲抑制。JNJ 不影响 Fmr1 KO 运动协调，但会损害 WT 表现。MPEP 改善了 Fmr1 KO 但不是 WT 小鼠的运动学习测量值。虽然 JNJ 和 MPEP 均可降低 Fmr1 KO 的听觉性癫痫发作，但 MPEP 完全消除了癫痫发作的表现。
这些数据表明，尽管操纵 mGluR1 或 mGluR5 都可以影响 Fmr1 KO 中的某些行为，但我们观察到对 mGluR5 减少的影响更大。
