Background

Depression is a common psychiatric disorder associated with defects in GABAergic (gamma-aminobutyric acidergic) neurotransmission. α-Dystroglycan (α-DG), a cell adhesion molecule known to be essential for skeletal muscle integrity, is also present at inhibitory synapses in the central nervous system and forms a structural element in certain synapses. However, the role of α-DG in the regulation of depressive-like behaviors remains largely unknown.

Methods

Depressive-like behaviors were induced by chronic social defeat stress in adult male mice. Surface protein was extracted by a biotin kit, and the expression of protein was detected by Western blotting. Intrahippocampal microinjection of the lentivirus or adeno-associated virus or agrin intervention was carried out using a stereotaxic instrument and followed by behavioral tests. Miniature inhibitory postsynaptic currents were recorded by whole-cell patch-clamp techniques.

Results

The expression of α-DG and glycosylated α-DG in the ventral hippocampus was significantly lower in chronic social defeat stress–susceptible male mice than in control mice, accompanied by a decreased surface expression of GABA_A receptor γ2 subunit and reduced GABAergic neurotransmission. RNA interference–mediated knockdown of Dag1 increased the susceptibility of mice to subthreshold stress. Both in vivo administration of agrin and overexpression of like-acetylglucosaminyltransferase ameliorated depressive-like behaviors and restored the decrease in surface expression of GABA_A receptor γ2 subunit and the amplitude of miniature inhibitory postsynaptic currents in chronic social defeat stress–exposed mice.

Conclusions

Our findings demonstrate that glycosylated α-DG plays a role in the pathophysiological process of depressive-like behaviors by regulating the surface expression of GABA_A receptor γ2 subunit and GABAergic neurotransmission in the ventral hippocampus.

中文翻译：

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腹侧海马中糖基化α-肌营养不良多糖的缺乏将γ-氨基丁酸A型受体的不稳定与雄性小鼠的抑郁样行为联系起来

背景

抑郁症是一种常见的精神疾病，与 GABA 能（γ-氨基丁酸能）神经传递缺陷有关。α-肌营养不良蛋白 (α-DG) 是一种已知对骨骼肌完整性至关重要的细胞粘附分子，它也存在于中枢神经系统的抑制性突触中，并在某些突触中形成结构元件。然而，α-DG 在调节抑郁样行为中的作用仍然很大程度上未知。

方法

成年雄性小鼠的慢性社交失败压力会诱发抑郁样行为。采用生物素试剂盒提取表面蛋白，Western blotting检测蛋白表达。使用立体定向仪器进行慢病毒或腺相关病毒或集聚蛋白干预的海马内显微注射，然后进行行为测试。通过全细胞膜片钳技术记录微型抑制性突触后电流。

结果

与对照小鼠相比，慢性社交失败压力易感雄性小鼠腹侧海马中α-DG和糖基化α-DG的表达显着低于对照小鼠，伴随着GABA _A受体γ2亚基的表面表达降低和GABA能神经传递降低。RNA 干扰介导的Dag1敲低增加了小鼠对阈下压力的敏感性。体内施用集聚蛋白和类似乙酰氨基葡萄糖转移酶的过表达都改善了抑郁样行为，并恢复了慢性社交失败应激小鼠中 GABA _A受体 γ2 亚基表面表达的降低和微型抑制性突触后电流的幅度。

结论

我们的研究结果表明，糖基化的 α-DG 通过调节腹侧海马GABA _A受体 γ2 亚基的表面表达和 GABA 能神经传递在抑郁样行为的病理生理过程中发挥作用。