The Autism-Related Protein PX-RICS Mediates GABAergic Synaptic Plasticity in Hippocampal Neurons and Emotional Learning in Mice.
The Autism-Related Protein PX-RICS Mediates GABAergic Synaptic Plasticity in Hippocampal Neurons and Emotional Learning in Mice.
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DOI：
10.1016/j.ebiom.2018.07.011
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发表时间：
2018-08
期刊：
影响因子：
11.1
通讯作者：
Akiyama T
中科院分区：
文献类型：
--
作者：
Nakamura T;Sakaue F;Nasu-Nishimura Y;Takeda Y;Matsuura K;Akiyama T
GABA 能功能障碍是许多神经发育和精神疾病的基础。 GABA 能突触在突触前和突触后水平均表现出多种形式的可塑性。 GABA 能突触后的 NMDA 受体 (NMDAR) 依赖性抑制性长时程增强 (iLTP) 需要通过促进胞吐作用来增加表面 GABAAR；然而，其调节机制和神经病理学意义仍不清楚。在此，我们报道自闭症相关蛋白 PX-RICS 参与 NMDAR 依赖性 GABAergic iLTP 期间驱动的 GABAAR 转运。化学诱导的 iLTP 引起野生型小鼠海马神经元表面 GABAAR 的快速增加，但在 PX-RICS/RICS 缺陷神经元中则不然。基因敲除和拯救研究表明，表面 GABAAR 的增加需要 PX-RICS/GABARAP/14-3-3 复合物。 iLTP 诱导 PX-RICS 的 CaMKII 依赖性磷酸化，以促进 PX-RICS-14-3-3 组装。值得注意的是，PX-RICS/RICS 缺陷小鼠表现出杏仁核依赖性恐惧学习能力受损，通过氯硝西泮增强 GABA 活性可以改善这种学习能力。我们的结果表明，PX-RICS 介导的 GABAAR 运输是 GABA 能可塑性的关键目标，其功能障碍导致自闭症的非典型情绪处理。自闭症相关蛋白 PX-RICS 参与化学诱导 iLTP 过程中 GABAAR 转运的促进。 PX-RICS/RICS-null 小鼠表现出杏仁核依赖性恐惧学习受损，通过增强 GABA 活性可以缓解这种情况。 PX-RICS 是 GABA 能可塑性的关键目标，其功能障碍会导致自闭症的非典型情绪处理。 PX-RICS 促进 GABAAR 在神经元中的组成型运输。 PX-RICS 缺陷会导致小鼠和雅各布森综合征患者出现类似自闭症的社交行为。 PX-RICS 中罕见的单核苷酸变异与非综合征性自闭症、精神分裂症和述情障碍有关。这些发现强烈表明 PX-RICS 功能障碍会损害大脑的社会情感处理。在这里，我们表明 PX-RICS 还参与 GABA 能突触可塑性的活动依赖性 GABAAR 运输，其功能障碍导致与杏仁核相关的情绪学习受损。阐明 GABA 能可塑性和社会情感学习之间的分子联系可能有助于更好地了解自闭症发病机制和治疗。
GABAergic dysfunction underlies many neurodevelopmental and psychiatric disorders. GABAergic synapses exhibit several forms of plasticity at both pre- and postsynaptic levels. NMDA receptor (NMDAR)–dependent inhibitory long-term potentiation (iLTP) at GABAergic postsynapses requires an increase in surface GABAARs through promoted exocytosis; however, the regulatory mechanisms and the neuropathological significance remain unclear. Here we report that the autism-related protein PX-RICS is involved in GABAAR transport driven during NMDAR–dependent GABAergic iLTP. Chemically induced iLTP elicited a rapid increase in surface GABAARs in wild-type mouse hippocampal neurons, but not in PX-RICS/RICS–deficient neurons. This increase in surface GABAARs required the PX-RICS/GABARAP/14–3-3 complex, as revealed by gene knockdown and rescue studies. iLTP induced CaMKII–dependent phosphorylation of PX-RICS to promote PX-RICS–14-3-3 assembly. Notably, PX-RICS/RICS–deficient mice showed impaired amygdala–dependent fear learning, which was ameliorated by potentiating GABAergic activity with clonazepam. Our results suggest that PX-RICS–mediated GABAAR trafficking is a key target for GABAergic plasticity and its dysfunction leads to atypical emotional processing underlying autism. The autism-related protein PX-RICS is involved in promoted GABAAR transport during chemically induced iLTP. PX-RICS/RICS-null mice show impaired amygdala–dependent fear learning, which is alleviated by enhancing GABAergic activity. PX-RICS is a key target for GABAergic plasticity and its dysfunction causes atypical emotional processing underlying autism. PX-RICS facilitates constitutive transport of GABAARs in neurons. PX-RICS deficiency leads to autistic-like social behaviors in mice and in patients with Jacobsen syndrome. Rare single-nucleotide variations in PX-RICS are linked to non-syndromic autism, schizophrenia and alexithymia. These findings strongly suggest that PX-RICS dysfunction impairs socio-emotional processing of the brain. Here we show that PX-RICS is also involved in activity–dependent GABAAR transport for GABAergic synaptic plasticity, and its dysfunction results in impaired emotional learning associated with the amygdale. Elucidation of the molecular link between GABAergic plasticity and socio-emotional learning could lead to a better understanding of autism pathogenesis and treatment.
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影响因子：
5.3
作者：
Flores CE;Méndez P
通讯作者：
Méndez P
影响因子：
5.7
作者：
Castillo PE;Chiu CQ;Carroll RC
通讯作者：
Carroll RC
DOI：
10.1007/bf00404119
发表时间：
1961-01-01
期刊：
PSYCHOPHARMACOLOGIA
影响因子：
--
作者：
EVANS, WO
通讯作者：
EVANS, WO
影响因子：
6.2
作者：
Chen CH;Huang CC;Cheng MC;Chiu YN;Tsai WC;Wu YY;Liu SK;Gau SS
通讯作者：
Gau SS
影响因子：
3.4
作者：
Kamal, A;Ramakers, GMJ;Gispen, WH
通讯作者：
Gispen, WH