Altered GluA1 (Gria1) Function and Accumbal Synaptic Plasticity in the ClockΔ19 Model of Bipolar Mania.
Altered GluA1 (Gria1) Function and Accumbal Synaptic Plasticity in the ClockΔ19 Model of Bipolar Mania.
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DOI：
10.1016/j.biopsych.2017.06.022
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发表时间：
2018-12-01
影响因子：
10.6
通讯作者：
McClung CA
中科院分区：
文献类型：
--
作者：
Parekh PK;Becker-Krail D;Sundaravelu P;Ishigaki S;Okado H;Sobue G;Huang Y;McClung CA
昼夜节律的紊乱与双相情感障碍（BD）的风险增加有关。此外，研究表明，昼夜节律蛋白CLOCK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。在ClockΔ19突变体和野生型（WT）小鼠中使用离体全细胞膜片钳电生理学，我们表征了兴奋性突触传递、强度和延髓核（NAc）神经元内在兴奋性的改变。我们进行了蛋白质交联和蛋白质印迹分析，以检查表面和细胞内的谷氨酸受体亚基，GLUA1，在NAc的水平和节奏。病毒介导的过表达的GluA1在NAc和行为测定也被使用。与WT小鼠相比，ClockΔ19小鼠在NAc中等多刺神经元（MSN）处显示出减少的AMPAR介导的兴奋性突触反应。这些改变可能是突触后的，因为在突变体中突触前谷氨酸释放到MSN上是不变的。此外，在ClockΔ19小鼠中，NAc表面蛋白水平和GLUA1的节律每日降低，与功能性突触反应降低一致。此外，我们观察到ClockΔ19 MSNs的显著超极化静息膜电位，表明内在兴奋性降低。最后，功能性GluA1在突变体的NAc中的过表达能够使小鼠处于躁狂样状态时增加的探索驱动和奖励敏感性行为正常化。总之，我们的研究结果表明，NAc兴奋性信号通过GLUA1的表达是不可或缺的时钟基因中断的影响，“躁狂样”的行为。
Disruptions in circadian rhythms are associated with an increased risk for bipolar disorder (BD). Moreover, studies show that the circadian protein CLOCK is involved in regulating monoaminergic systems and mood-related behavior. However the molecular and synaptic mechanisms underlying this relationship remain poorly understood. Using ex vivo whole cell patch clamp electrophysiology in ClockΔ19 mutant and wildtype (WT) 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 GluA1 in the NAc and behavioral assays were also used. Compared with WT mice, ClockΔ19 mice display reduced AMPAR-mediated excitatory synaptic responses at NAc medium spiny neurons (MSNs). These alterations are likely postsynaptic as presynaptic release of glutamate onto MSNs is unaltered in mutants. Additionally, NAc surface protein levels and the rhythm of GLUA1 are decreased in ClockΔ19 mice diurnally, consistent with reduced functional synaptic response. Furthermore, we observed a significantly hyperpolarized resting membrane potential of ClockΔ19 MSNs suggesting lowered intrinsic excitability. Lastly, overexpression of functional GluA1 in the NAc of mutants was able to normalize increased exploratory drive and reward sensitivity behavior when mice are in a manic-like state. Together, our findings demonstrate that NAc excitatory signaling via GLUA1 expression is integral to the effects of Clock gene disruption on “manic-like” behaviors.
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影响因子：
16.2
作者：
Lüscher C;Malenka RC
通讯作者：
Malenka RC
影响因子：
4.7
作者：
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通讯作者：
Thomas MJ
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作者：
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作者：
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Kupfer, DJ
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作者：
Coque, Laurent;Mukherjee, Shibani;McClung, Colleen A.
通讯作者：
McClung, Colleen A.