Shisa6 mediates cell-type specific regulation of depression in the nucleus accumbens.
Shisa6 mediates cell-type specific regulation of depression in the nucleus accumbens.
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DOI：
10.1038/s41380-021-01217-8
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发表时间：
2021-12
影响因子：
11
通讯作者：
Ferguson D
中科院分区：
文献类型：
--
作者：
Kim HD;Wei J;Call T;Quintus NT;Summers AJ;Carotenuto S;Johnson R;Ma X;Xu C;Park JG;Qiu S;Ferguson D
抑郁症是残疾的主要原因，并产生巨大的健康和经济负担。目前抑郁症的治疗方法在很大程度上是无效的，超过50%的患者有症状，主要是因为抗抑郁药的非选择性和广泛作用。因此，迫切需要设计和开发治疗抑郁症的新疗法。鉴于大脑的异质性和复杂性，识别负责产生抑郁样行为的特定细胞类型内的分子机制将促进治疗的发展。在奖赏回路中，延髓核（NAc）是抑郁症病理生理学的关键脑区，可能基于D1或D2中型棘神经元（MSNs）的差异活动。在这里，我们报告了一个电路和细胞类型特异性分子靶点抑郁症，Shisa 6，最近被定义为AMPAR组分，它只在易感小鼠NAc的D1-MSNs中增加。使用Ribotag方法，我们通过RNA测序在抑郁症、慢性社会失败压力（CSDS）小鼠模型后剖析了D1和D2-MSN的转录谱。生物信息学分析确定了可能导致抑郁症发病机制的细胞类型特异性基因，包括Shisa 6。我们发现腹侧被盖区（VTA）到NAc回路的选择性光遗传学激活增加了D1-MSN中Shisa 6的表达。Shisa 6特异性地位于D1-MSN的兴奋性突触中，并增加神经元的兴奋性，从而促进小鼠的焦虑和抑郁样行为。Shisa 6的细胞类型和回路特异性作用直接调节传递厌恶信息的兴奋性突触，将该蛋白质鉴定为抑郁症中异常回路功能的潜在快速抗抑郁靶点。
Depression is the leading cause of disability and produces enormous health and economic burdens. Current treatment approaches for depression are largely ineffective and leave more than 50% of patients symptomatic, mainly because of non-selective and broad action of antidepressants. Thus, there is an urgent need to design and develop novel therapeutics to treat depression. Given the heterogeneity and complexity of the brain, identification of molecular mechanisms within specific cell-types responsible for producing depression-like behaviors will advance development of therapies. In the reward circuitry, the nucleus accumbens (NAc) is a key brain region of depression pathophysiology, possibly based on differential activity of D1- or D2- medium spiny neurons (MSNs). Here we report a circuit- and cell-type specific molecular target for depression, Shisa6, recently defined as an AMPAR component, which is increased only in D1-MSNs in the NAc of susceptible mice. Using the Ribotag approach, we dissected the transcriptional profile of D1- and D2-MSNs by RNA sequencing following a mouse model of depression, chronic social defeat stress (CSDS). Bioinformatic analyses identified cell-type specific genes that may contribute to the pathogenesis of depression, including Shisa6. We found selective optogenetic activation of the ventral tegmental area (VTA) to NAc circuit increases Shisa6 expression in D1-MSNs. Shisa6 is specifically located in excitatory synapses of D1-MSNs and increases excitability of neurons, which promotes anxiety- and depression-like behaviors in mice. Cell-type and circuit-specific action of Shisa6, which directly modulates excitatory synapses that convey aversive information, identifies the protein as a potential rapid-antidepressant target for aberrant circuit function in depression.
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