Generation of silent synapses in dentate gyrus correlates with development of alcohol addiction
Generation of silent synapses in dentate gyrus correlates with development of alcohol addiction
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DOI：
10.1038/s41386-018-0119-4
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发表时间：
2018-09-01
影响因子：
7.6
通讯作者：
Radwanska, Kasia
中科院分区：
文献类型：
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作者：
Beroun, Anna;Nalberczak-Skora, Maria;Radwanska, Kasia
酒精成瘾背后的大脑回路和突触过程目前是深入研究的主题。在这里，我们重点关注海马回路，并表明在呈现酒精相关线索期间齿状回（DG）的化学遗传学抑制对小鼠行为具有长期持续的影响。 DG 抑制会增强寻酒和饮酒，表明 DG 调节与成瘾相关的行为。为了检验这一假设，我们对 DG 的颗粒细胞进行全细胞膜片钳记录，并寻找酒精成瘾的电生理相关性。我们观察到，与酒精相关的提示光的出现会导致重新寻找酒精，从而导致沉默突触的产生，而这些突触缺乏功能性 AMPA 受体。此外，利用人类的成瘾标准，我们将控制饮酒的小鼠与那些经历成瘾转变的小鼠区分开来，发现由酒精暗示诱导的沉默突触水平在成瘾的小鼠中特别增加。由于此时包含突触的树突棘的总水平是恒定的，因此我们的数据表明，在提示复发期间，通向 DG 的穿通路径的突触被削弱。最后，我们证明，阿坎酸（一种限制成瘾者饮酒和寻求酒精的药物）可以防止在出现酒精相关线索时 DG 中产生沉默突触。总而言之，我们的数据表明，提示复发时 DG 突触的减弱会导致持续的酒精成瘾相关行为。
The brain circuits and synaptic processes that underlie alcohol addiction are currently the subject of intensive research. Here we focus on hippocampal circuitry and show that chemogenetic inhibition of dentate gyrus (DG) during presentation of alcohol-associated cues has long-lasting effects on mice behavior. DG inhibition enhances alcohol seeking and drinking, suggesting that DG regulates addiction-related behaviors. To test this hypothesis, we perform whole-cell patch-clamp recordings from the granule cells of DG and look for electrophysiological correlates of alcohol addiction. We observe that presentation of alcohol-associated cue light that induces relapse to alcohol-seeking results in generation of silent synapses, that lack functional AMPA receptors. Furthermore, using human criteria of addiction, we differentiate mice controlling their alcohol consumption from those that undergo transition to addiction to discover that the levels of silent synapses induced by alcohol cues are specifically increased in the addicted mice. As the total level of dendritic spines that harbor synapses is constant at this time point, our data indicate that synapses of perforant path to DG are weakened during cue relapse. Finally we demonstrate that, acamprosate, a drug that limits alcohol drinking and seeking in addicts, prevents generation of silent synapses in DG upon presentation of alcohol-associated cues. Altogether, our data suggest that weakening of DG synapses upon cue relapse contributes to persistent alcohol addiction-related behaviors.