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

Abstract

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.

Keywords: Agrin; CSDS; Depression; GABA(A) receptor; LARGE (like-acetylglucosaminyltransferase); Ventral hippocampus; α-Dystroglycan.