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Altered GluA1 ( Gria1 ) Function and Accumbal Synaptic Plasticity in the Clock Δ19 Model of Bipolar Mania
Biological Psychiatry ( IF 10.6 ) Pub Date : 2018-12-01 , DOI: 10.1016/j.biopsych.2017.06.022
Puja K. Parekh , Darius Becker-Krail , Poornima Sundaravelu , Shinsuke Ishigaki , Haruo Okado , Gen Sobue , Yanhua Huang , Colleen A. McClung

BACKGROUND Disruptions in circadian rhythms are associated with an increased risk for bipolar disorder. Moreover, studies show that the circadian protein CLOCK (circadian locomotor output cycles kaput) is involved in regulating monoaminergic systems and mood-related behavior. However, the molecular and synaptic mechanisms underlying this relationship remain poorly understood. METHODS Using ex vivo whole-cell patch-clamp electrophysiology in ClockΔ19 mutant and wild-type mice we characterized alterations in excitatory synaptic transmission, strength, and intrinsic excitability of nucleus accumbens (NAc) neurons. We performed protein crosslinking and Western blot analysis to examine surface and intracellular levels and rhythm of the glutamate receptor subunit, GluA1, in the NAc. Viral-mediated overexpression of Gria1 in the NAc and behavioral assays were also used. RESULTS Compared with wild-type mice, ClockΔ19 mice display reduced alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor-mediated excitatory synaptic responses at NAc medium spiny neurons. These alterations are likely postsynaptic, as presynaptic release of glutamate onto medium spiny neurons is unaltered in mutant mice. Additionally, NAc surface protein levels and the rhythm of GRIA1 are decreased in ClockΔ19 mice diurnally, consistent with reduced functional synaptic response. Furthermore, we observed a significantly hyperpolarized resting membrane potential of ClockΔ19 medium spiny neurons, suggesting lowered intrinsic excitability. Last, overexpression of functional Gria1 in the NAc of mutant mice was able to normalize increased exploratory drive and reward sensitivity behavior when mice are in a manic-like state. CONCLUSIONS Together, our findings demonstrate that NAc excitatory signaling via Gria1 expression is integral to the effects of Clock gene disruption on manic-like behaviors.

中文翻译:

双极躁狂症时钟Δ19模型中GluA1(Gria1)功能和累积突触可塑性的改变

背景昼夜节律的紊乱与双相情感障碍的风险增加有关。此外,研究表明,昼夜节律蛋白 CLOCK(昼夜节律运动输出周期 kaput)参与调节单胺能系统和情绪相关行为。然而,这种关系背后的分子和突触机制仍然知之甚少。方法在 ClockΔ19 突变体和野生型小鼠中使用离体全细胞膜片钳电生理学,我们表征了伏隔核 (NAc) 神经元的兴奋性突触传递、强度和内在兴奋性的改变。我们进行了蛋白质交联和蛋白质印迹分析,以检查 NAc 中谷氨酸受体亚基 GluA1 的表面和细胞内水平和节律。还使用了病毒介导的 Gria1 在 NAc 和行为分析中的过度表达。结果 与野生型小鼠相比,ClockΔ19 小鼠在 NAc 中等多刺神经元处显示出降低的 α-氨基-3-羟基-5-甲基-4-异恶唑丙酸受体介导的兴奋性突触反应。这些改变很可能是突触后的,因为在突变小鼠中谷氨酸在突触前释放到中等多刺神经元上没有改变。此外,ClockΔ19 小鼠的 NAc 表面蛋白水平和 GRIA1 节律每天都会降低,这与功能性突触反应的降低一致。此外,我们观察到 ClockΔ19 中等多刺神经元的静息膜电位显着超极化,表明内在兴奋性降低。最后的,当小鼠处于躁狂状态时,突变小鼠 NAc 中功能性 Gria1 的过度表达能够使增加的探索驱动和奖励敏感性行为正常化。结论 总之,我们的研究结果表明,通过 Gria1 表达的 NAc 兴奋性信号传导是 Clock 基因破坏对躁狂样行为的影响的组成部分。
更新日期:2018-12-01
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