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PLCß介导的钙调腺苷酸环化酶在突触可塑性相关基因转录中的作用和FE65对海马依赖学习及LTP的调节
Alternative TitleRegulation of ACI by Gq in transcription and FE65 in learning and LTP
王彦
Subtype博士
Thesis Advisor孙中生
2009-12-30
Degree Grantor中国科学院心理研究所
Place of Conferral心理研究所
Keyword腺苷酸环化酶 转录 I组代谢型谷氨酸受体PLCß FE65 学习 长时程增强
Abstract基因调控是突触可塑性活动依赖的变化所必需的。本研究中,我们分别研究了转录依赖和转录非依赖机制在长时信息储存中的作用。神经系统中,I 组代谢型谷氨酸受体参与了学习记忆、精神失常、药物成瘾和痛觉等众多生理过程。在皮质神经元中,I 组代谢型谷氨酸受体通过活化PLCß,激活多种钙离子调节的信号通路,引起的ERK和CREB 磷酸化,在基因转录中发挥重要作用。更为重要的是,通过运用基因敲除方法,我们还观察到I 组代谢型谷氨酸受体通过Gq蛋白,激活Ca调腺苷酸环化酶1,参与可塑性相关的基因转录的调节。此外,我们还发现了一个新的可被I 组代谢型谷氨酸受体活化诱导的基因,Arc。Arc的表达与突触活动紧密相关。ERK信号通路在I组代谢型谷氨酸受体调节的Arc转录中起着关键的作用。 在长时信息储存转录非依赖机制研究中,我们以参与老年痴呆病理过程的FE65为主要对象。FE65主要表达在大脑,与β淀粉状前体蛋白(APP)的C末端结合。我们观察了FE65特定同源异构体敲除小鼠(p97FE65-/-) 海马依赖的记忆和体内海马CA1区长时程增强(LTP)。我们发现, p97FE65敲除小鼠的主要缺陷是与短时记忆或获得相关的,这个过程是不需要转录调节的。与此一致,在谢弗平行纤维-海马CA1区兴奋性突触后电位突触,p97FE65敲除小鼠表现出早时相LTP缺陷。
Other AbstractGene regulation is required for activity-dependent changes in synaptic plasticity and remodeling. The metabotropic glutamate receptors (mGluRs) contribute to different brain functions, including learning/memory, mental disorders, drug addiction, and persistent pain in the CNS. We found that Gp I mGluRs activate PLCß through Gq and then lead to activation of several calcium-dependent signaling pathways, including ERK, which play an important role in gene transcription. These findings support a calcium-dependent role for Gq in release of Calcium and activation of calcium-stimulated adenylyl cyclases I in activity-dependent transcription in response to application of group I metabotropic glutamate receptors agonist and may provide insights into group I mGluRs-dependent synaptic plasticity through MAP kinases signaling. Moreover, the present study investigated the transcription-dependent changes of Arc in response to the activation of group I mGluRs and suggested the central role of ERK1/2 in group I mGluR-mediated Arc transcription. Further, we selected APP-interaction protein FE65 to investigate the mechanism of transcription-related process in synaptic plasticity. FE65 is expressed predominantly in the brain, and interacts with the C-terminal domain of β-amyloid precursor protein (APP). We examined hippocampus-dependent memory and in vivo long-term potentiation (LTP) at the CA1 synapses with the isoform-specific FE65 knock-out (p97FE65-/-) mice. p97FE65 knock-out mice showed impaired short-term memory for both TDPA and CFC when tested 10min after training, which is transcription-independent. Consistently, at the Schaffer collateral-CA1 synapses, p97FE65 knock-out mice showed defective early phase LTP. These results demonstrate novel roles of FE65 in synaptic plasticity, acquisition, and retention for certain forms of memory formation.
Pages131
Language中文
Document Type学位论文
Identifierhttp://ir.psych.ac.cn/handle/311026/4736
Collection中国科学院心理研究所回溯数据库(1956-2010)
Recommended Citation
GB/T 7714
王彦. PLCß介导的钙调腺苷酸环化酶在突触可塑性相关基因转录中的作用和FE65对海马依赖学习及LTP的调节[D]. 心理研究所. 中国科学院心理研究所,2009.
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