Deletion of adenosine A2A receptors from astrocytes disrupts glutamate homeostasis leading to psychomotor and cognitive impairment: relevance to schizophrenia.
Deletion of adenosine A2A receptors from astrocytes disrupts glutamate homeostasis leading to psychomotor and cognitive impairment: relevance to schizophrenia.
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DOI：
10.1016/j.biopsych.2015.02.026
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发表时间：
2015-12-01
影响因子：
10.6
通讯作者：
Chen JF
中科院分区：
文献类型：
--
作者：
Matos M;Shen HY;Augusto E;Wang Y;Wei CJ;Wang YT;Agostinho P;Boison D;Cunha RA;Chen JF
腺苷 A2A 受体 (A2AR) 调节多巴胺和谷氨酸信号传导，从而可能影响与精神分裂症相关的一些精神运动和认知过程。由于星形胶质细胞 A2AR 调节谷氨酸的可用性，我们假设它们可能在导致精神分裂症发展的一些过程中发挥前所未有的作用，我们使用星形胶质细胞中选择性删除 A2AR 的小鼠系（Gfa2-A2AR 敲除 [KO] 小鼠）进行了研究。我们检查了 Gfa2-A2AR KO 小鼠的行为，这些行为被认为概括了精神分裂症的一些特征，即增强MK-801 精神运动反应（阳性症状）和工作记忆下降（认知症状）此外，我们探讨了谷氨酸能回路中的神经化学变化，评估谷氨酸的摄取和释放以及定义谷氨酸信号传导的关键蛋白（谷氨酸转运蛋白-I [GLT-I]、N-甲基-D-天冬氨酸受体 [NMDA-R] 和）的水平。 α-3-羟基-5-甲基-4-异恶唑丙酸受体[AMPA-R]）提供了对所遇到的表型的机制理解我们表明，Gfa2-A2AR KO小鼠表现出增强的MK-801精神运动反应和降低的工作记忆；这伴随着谷氨酸稳态的破坏，其特征是异常的GLT-I活性、突触前谷氨酸释放、NMDA-R。 2B 亚基上调，以及 AMPA-R 内化增加。 因此，选择性 GLT-1 抑制或 GluR1/2 内吞作用的阻断阻止了 Gfa2-A2AR KO 小鼠（即伏隔核中）的精神运动和认知表型。这些结果表明，星形胶质细胞 A2AR 的功能障碍通过控制 GLT-1 活性触发星形胶质细胞与神经元的通讯波，导致谷氨酸被破坏。稳态，被认为是与精神分裂症相关的几种内表型的基础。
Adenosine A2A receptors (A2AR) modulate dopamine and glutamate signaling and thereby may influence some of the psychomotor and cognitive processes associated with schizophrenia. Because astroglial A2AR regulate the availability of glutamate, we hypothesized that they might play an unprecedented role in some of the processes leading to the development of schizophrenia, which we investigated using a mouse line with a selective deletion of A2AR in astrocytes (Gfa2-A2AR knockout [KO] mice]. We examined Gfa2-A2AR KO mice for behaviors thought to recapitulate some features of schizophrenia, namely enhanced MK-801 psychomotor response (positive symptoms) and decreased working memory (cognitive symptoms). In addition, we probed for neurochemical alterations in the glutamatergic circuitry, evaluating glutamate uptake and release and the levels of key proteins defining glutamatergic signaling (glutamate transporter-I [GLT-I], N-methyl-D-aspartate receptors [NMDA-R] and α-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors [AMPA-R]) to provide a mechanistic understanding of the phenotype encountered. We show that Gfa2-A2AR KO mice exhibited enhanced MK-801 psychomotor response and decreased working memory; this was accompanied by a disruption of glutamate homeostasis characterized by aberrant GLT-I activity, increased presynaptic glutamate release, NMDA-R 2B subunit upregulation, and increased internalization of AMPA-R. Accordingly, selective GLT-I inhibition or blockade of GluR1/2 endocytosis prevented the psychomotor and cognitive phenotypes in Gfa2-A2AR KO mice, namely in the nucleus accumbens. These results show that the dysfunction of astrocytic A2AR, by controlling GLT-I activity, triggers an astrocyte-to-neuron wave of communication resulting in disrupted glutamate homeostasis, thought to underlie several endophenotypes relevant to schizophrenia.