Altered phosphorylation, electrophysiology, and behavior on attenuation of PDE4B action in hippocampus.
Altered phosphorylation, electrophysiology, and behavior on attenuation of PDE4B action in hippocampus.
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DOI：
10.1186/s12868-017-0396-6
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发表时间：
2017-12-02
期刊：
影响因子：
2.4
通讯作者：
Bolger GB
中科院分区：
文献类型：
--
作者：
Campbell SL;van Groen T;Kadish I;Smoot LHM;Bolger GB
PDE 4环核苷酸磷酸二酯酶调节中枢神经系统中3′，5′ cAMP的丰度，从而调节PKA活性和CREB的磷酸化，这与学习记忆、抑郁等功能有关。PDE 4亚型PDE 4 B1也与DISC 1蛋白相互作用，涉及神经发育和行为障碍。PDE 4 B1的细胞功能已被广泛研究，但其在完整生物体中的功能尚未探索。为了特异性破坏PDE 4 B1，我们开发了在海马和前脑中表达PDE 4 B1-D564 A转基因的小鼠。转基因小鼠海马CREB和ERK 1/2磷酸化增强。转基因小鼠海马神经发生增加。海马电生理研究表明，增加基线突触传递和增强LTP在雄性转基因小鼠。在行为上，雄性转基因小鼠在长时间的旷场测试中表现出活动增加，但在高架十字迷宫、悬尾或强迫游泳测试中，雄性和雌性转基因小鼠均未表现出可检测到的焦虑样行为或抗抑郁作用。两种性别在关联恐惧条件反射方面均未显示出任何显著差异，或在前脉冲抑制方面均未显示出任何明显异常。这些数据支持使用异构体选择性的方法来研究PDE 4 B1在CNS中的功能，并表明PDE 4 B1在突触可塑性和行为中的可能作用。它们还为开发小分子PDE 4 B1选择性抑制剂提供了额外的理论依据和改进的方法，这些抑制剂在认知，记忆，情绪和情感障碍中具有潜在的功能。
PDE4 cyclic nucleotide phosphodiesterases regulate 3′, 5′ cAMP abundance in the CNS and thereby regulate PKA activity and phosphorylation of CREB, which has been implicated in learning and memory, depression and other functions. The PDE4 isoform PDE4B1 also interacts with the DISC1 protein, implicated in neural development and behavioral disorders. The cellular functions of PDE4B1 have been investigated extensively, but its function(s) in the intact organism remained unexplored. To specifically disrupt PDE4B1, we developed mice that express a PDE4B1-D564A transgene in the hippocampus and forebrain. The transgenic mice showed enhanced phosphorylation of CREB and ERK1/2 in hippocampus. Hippocampal neurogenesis was increased in the transgenic mice. Hippocampal electrophysiological studies showed increased baseline synaptic transmission and enhanced LTP in male transgenic mice. Behaviorally, male transgenic mice showed increased activity in prolonged open field testing, but neither male nor female transgenic mice showed detectable anxiety-like behavior or antidepressant effects in the elevated plus-maze, tail-suspension or forced-swim tests. Neither sex showed any significant differences in associative fear conditioning or showed any demonstrable abnormalities in pre-pulse inhibition. These data support the use of an isoform-selective approach to the study of PDE4B1 function in the CNS and suggest a probable role of PDE4B1 in synaptic plasticity and behavior. They also provide additional rationale and a refined approach to the development of small-molecule PDE4B1-selective inhibitors, which have potential functions in disorders of cognition, memory, mood and affect.
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影响因子：
4.8
作者：
Bolger GB;Dunlop AJ;Meng D;Day JP;Klussmann E;Baillie GS;Adams DR;Houslay MD
通讯作者：
Houslay MD
影响因子：
4.1
作者：
Bolger, Graeme B.;Baillie, George S.;Houslay, Miles D.
通讯作者：
Houslay, Miles D.
影响因子：
16.2
作者：
Ahn, S;Ginty, DD;Linden, DJ
通讯作者：
Linden, DJ
影响因子：
4.1
作者：
Baillie, George S.;Adams, David R.;Houslay, Miles D.
通讯作者：
Houslay, Miles D.
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影响因子：
5.3
作者：
Brai E;Marathe S;Astori S;Fredj NB;Perry E;Lamy C;Scotti A;Alberi L
通讯作者：
Alberi L