Deficiency of Glycosylated α-Dystroglycan in Ventral Hippocampus Bridges the Destabilization of Gamma-Aminobutyric Acid Type A Receptors With the Depressive-like Behaviors of Male Mice

• Published in: Biological psychiatry (1969) 2022-03, Vol.91 (6), p.593-603
• Main Authors: Xie, Wen-Long, Zheng, Hui-Ling, Li, Hou-Hong, Lu, Jia-Jing, Xue, Shi-Ge, Luo, Yi, Ma, Cong, Liu, Jian-Feng, Hu, Zhuang-Li, Ni, Lan, Jin, You, Wang, Fang, Chen, Jian-Guo
• Format: Article
• Language: English
• Subjects: Agrin; CSDS; Depression; GABAA receptor; LARGE (like-acetylglucosaminyltransferase); Ventral hippocampus; α-Dystroglycan
• ISSN: 0006-3223; 1873-2402
• DOI: 10.1016/j.biopsych.2021.10.022

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. 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. 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 GABAA 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 GABAA receptor γ2 subunit and the amplitude of miniature inhibitory postsynaptic currents in chronic social defeat stress–exposed mice. Our findings demonstrate that glycosylated α-DG plays a role in the pathophysiological process of depressive-like behaviors by regulating the surface expression of GABAA receptor γ2 subunit and GABAergic neurotransmission in the ventral hippocampus.