Chronic mild stress alters synaptic plasticity in the nucleus accumbens through GSK3β-dependent modulation of Kv4.2...

Although major depressive disorder (MDD) is highly prevalent, its pathophysiology is poorly understood. Recent evidence suggests that glycogen-synthase kinase 3β (GSK3β) plays a key role in memory formation, yet its role in mood regulation remains controversial. Here, we investigated whether GSK3β activity in the nucleus accumbens (NAc) is associated with depression-like behaviors and synaptic plasticity. We performed whole-cell patch-clamp recordings of medium spiny neurons (MSNs) in the NAc and determined the role of GSK3β in spike timing-dependent long-term potentiation (tLTP) in the chronic unpredictable mild stress (CUMS) mouse model of depression. To assess the specific role of GSK3β in tLTP, we used in vivo genetic silencing by an adeno-associated viral vector (AAV2) short hairpin RNA against GSK3β. In addition, we examined the role of the voltage-gated potassium Kv4.2 subunit, a molecular determinant of A-type K⁺ currents, as a potential downstream target of GSK3β. We found increased levels of active GSK3β and augmented tLTP in CUMS mice, a phenotype that was prevented by selective GSK3β knockdown. Furthermore, knockdown of GSK3β in the NAc ameliorated depressive-like behavior in CUMS mice. Electrophysiological, immunohistochemical, biochemical, and pharmacological experiments revealed that inhibition of the Kv4.2 channel through direct phosphorylation at Ser-616 mediated the GSK3β-dependent tLTP changes in CUMS mice. Our results identify GSK3β regulation of Kv4.2 channels as a molecular mechanism of MSN maladaptive plasticity underlying depression-like behaviors and suggest that the GSK3β-Kv4.2 axis may be an attractive therapeutic target for MDD.