Dominant-Negative Attenuation of cAMP-Selective Phosphodiesterase PDE4D Action Affects Learning and Behavior
Dominant-Negative Attenuation of cAMP-Selective Phosphodiesterase PDE4D Action Affects Learning and Behavior
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DOI：
10.3390/ijms21165704
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发表时间：
2020-08-01
影响因子：
5.6
通讯作者：
van Groen, Thomas
中科院分区：
文献类型：
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作者：
Bolger, Graeme B.;Smoot, Lisa High Mitchell;van Groen, Thomas
PDE 4环核苷酸磷酸二酯酶降低CNS中的3 '，5 ' cAMP水平，从而调节PKA活性和CREB的磷酸化，这是抑郁、认知和学习与记忆的基础。PDE 4亚型PDE 4D 5与信号蛋白β-抑制蛋白2和RACK 1相互作用，后者是β 2-肾上腺素能和其他信号转导途径的调节剂。人类PDE 4D基因突变易患肢端骨发育不全，并伴有认知和行为缺陷。为了靶向PDE 4D 5，我们开发了在脑中表达PDE 4D 5-D556 A显性阴性转基因的小鼠。在Morris水迷宫中，雄性转基因小鼠表现出明显的海马区依赖性空间学习缺陷。相比之下，联想学习，如在恐惧条件反射试验中所测定的，似乎不受影响。雄性转基因小鼠在长时间（2小时）的旷场试验中表现出增强的活性，而雌性转基因小鼠在相同的试验中表现出降低的活性。转基因小鼠在前脉冲抑制中没有表现出明显的异常。在高架十字迷宫中测得的焦虑样行为也没有可检测到的差异。这些数据支持使用显性-阴性方法研究PDE 4D 5在CNS中的功能，特别是在学习和记忆中的功能。
PDE4 cyclic nucleotide phosphodiesterases reduce 3 ', 5 ' cAMP levels in the CNS and thereby regulate PKA activity and the phosphorylation of CREB, fundamental to depression, cognition, and learning and memory. The PDE4 isoform PDE4D5 interacts with the signaling proteins beta-arrestin2 and RACK1, regulators of beta(2)-adrenergic and other signal transduction pathways. Mutations inPDE4Din humans predispose to acrodysostosis, associated with cognitive and behavioral deficits. To target PDE4D5, we developed mice that express a PDE4D5-D556A dominant-negative transgene in the brain. Male transgenic mice demonstrated significant deficits in hippocampus-dependent spatial learning, as assayed in the Morris water maze. In contrast, associative learning, as assayed in a fear conditioning assay, appeared to be unaffected. Male transgenic mice showed augmented activity in prolonged (2 h) open field testing, while female transgenic mice showed reduced activity in the same assay. Transgenic mice showed no demonstrable abnormalities in prepulse inhibition. There was also no detectable difference in anxiety-like behavior, as measured in the elevated plus-maze. These data support the use of a dominant-negative approach to the study of PDE4D5 function in the CNS and specifically in learning and memory.