Chronic mild stress alters synaptic plasticity in the nucleus accumbens through GSK3β-dependent modulation of Kv4.2 channels
Chronic mild stress alters synaptic plasticity in the nucleus accumbens through GSK3β-dependent modulation of Kv4.2 channels
复制标题
DOI：
10.1073/pnas.1917423117
复制
发表时间：
2020-04-07
影响因子：
11.1
通讯作者：
Grassi, Claudio
中科院分区：
文献类型：
--
作者：
Aceto, Giuseppe;Colussi, Claudia;Grassi, Claudio
虽然重性抑郁症（MDD）是非常普遍的，其病理生理学知之甚少。最近的证据表明，糖原合成酶激酶3 β（GSK 3 β）在记忆形成中起着关键作用，但其在情绪调节中的作用仍然存在争议。在这里，我们研究了是否GSK 3 β活性在核丘脑（NAc）与抑郁样行为和突触可塑性。我们进行了全细胞膜片钳记录中型多刺神经元（MSN）在NAc和确定的作用，GSK 3 β在尖峰时间依赖性长时程增强（tLTP）在慢性不可预测的轻度应激（MASS）抑郁症小鼠模型。为了评估GSK 3 β在tLTP中的特定作用，我们使用腺相关病毒载体（AAV 2）短发夹RNA对GSK 3 β进行体内遗传沉默。此外，我们研究了电压门控钾Kv4.2亚基（A型K+电流的分子决定因素）作为GSK 3 β潜在下游靶点的作用。我们发现，活性GSK 3 β的水平增加，并增强了tLTP在GISKS小鼠，一种表型，这是防止选择性GSK 3 β敲低。此外，NAc中GSK 3 β的敲低可改善CUMS小鼠的抑郁样行为。电生理学、免疫组织化学、生物化学和药理学实验表明，通过Ser-616直接磷酸化抑制Kv4.2通道介导了GSK 3 β依赖性tLTP的变化。我们的研究结果表明，GSK 3 β调节Kv4.2通道作为MSN适应不良可塑性的分子机制，其基础是抑郁样行为，并表明GSK 3 β-Kv4.2轴可能是MDD的一个有吸引力的治疗靶点。
Although major depressive disorder (MDD) is highly prevalent, its pathophysiology is poorly understood. Recent evidence suggests that glycogen-synthase kinase 3 beta (GSK3 beta) plays a key role in memory formation, yet its role in mood regulation remains controversial. Here, we investigated whether GSK3 beta 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 GSK3 beta 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 GSK3 beta in tLTP, we used in vivo genetic silencing by an adeno-associated viral vector (AAV2) short hairpin RNA against GSK3 beta. 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 GSK3 beta. We found increased levels of active GSK3 beta and augmented tLTP in CUMS mice, a phenotype that was prevented by selective GSK3 beta knockdown. Furthermore, knockdown of GSK3 beta 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 GSK3 beta-dependent tLTP changes in CUMS mice. Our results identify GSK3 beta regulation of Kv4.2 channels as a molecular mechanism of MSN maladaptive plasticity underlying depression-like behaviors and suggest that the GSK3 beta-Kv4.2 axis may be an attractive therapeutic target for MDD.