do Rêgo Ana Gabriela de Oliveira, D'Amico Francesca, D'Angelo Vincenza, Cardarelli Silvia, Cutuli Debora, Decandia Davide, Landolfo Eugenia, Petrosini Laura, Pellegrini Manuela, D'Amelio Marcello, Mercuri Nicola Biagio, Giorgi Mauro, Sancesario Giuseppe
Department of Biology and Biotechnology "Charles Darwin", Sapienza University, 00185 Rome, Italy.
Department of Systems Medicine, Tor Vergata University, 00133 Rome, Italy.
Neurobiol Dis. 2025 Feb;205:106781. doi: 10.1016/j.nbd.2024.106781. Epub 2024 Dec 27.
Phosphodiesterase 2 A (PDE2A) function is stimulated by cGMP to catabolize cAMP. However, neurological and neurochemical effects of PDE2A deficiency are poorly understood. To address this gap, we studied behavioral characteristics and cerebral morpho-chemical changes of adult male heterozygous C57BL/6-PDE2A+/- (HET), and wild type C57BL/6-PDE2A+/+ (WT) mice. Behavioral functions of mice were evaluated by a wide test battery. HET mice exhibited greater tendency to explore novel environments in comparison to WT mice, but spatial working memory, anxiety, and sociability were similar in adult HET and WT mice. In HET mice, PDE2A mRNA, PDE2A protein expression, and cGMP hydrolyzing enzymatic activity were consistently reduced by about 50 %. Consequently, the cyclic nucleotide levels were significantly increased in HET mice, but unexpectedly the mean percentage variation was higher for cGMP equal to 153.23 %, and lower for cAMP equal to 16.41 %. Therefore, to try to explain the preponderant increase of cGMP to cAMP we evaluated other PDE enzymes functionally related to PDE2A. Surprisingly, results were quite contradictory: in HET mice protein levels of the other dual-specificity enzyme PDE3A and PDE10A were reduced, whereas the expressions of PDE5A and PDE9A that selectively hydrolyze cGMP were increased. Therefore, we investigated the involvement of neuronal nitric oxide synthase (nNOS) expression, as determinant of a possible increased synthesis of NO/cGMP signaling. Interestingly, in HET mice the expression level of brain nNOS, measured by western blot and immune-histochemistry was significantly increased, particularly in interneurons from the striatum. In conclusion, the deficiency of PDE2A could be compensated in the striatum by upregulating nNOS/NO/cGMP pathway, which in turn likely upregulates PDE2A-dependent cAMP hydrolysis. The neuroanatomical correlation between striatal nNOS upregulation and the behavioral phenotype of increased exploratory behavior in HET mice is advanced.
磷酸二酯酶2A（PDE2A）的功能受环鸟苷酸（cGMP）刺激，可分解环磷酸腺苷（cAMP）。然而，PDE2A缺乏的神经学和神经化学效应尚不清楚。为了填补这一空白，我们研究了成年雄性杂合子C57BL/6-PDE2A+/-（HET）和野生型C57BL/6-PDE2A+/+（WT）小鼠的行为特征和脑形态化学变化。通过广泛的测试组评估小鼠的行为功能。与WT小鼠相比，HET小鼠表现出更强的探索新环境的倾向，但成年HET小鼠和WT小鼠的空间工作记忆、焦虑和社交能力相似。在HET小鼠中，PDE2A信使核糖核酸（mRNA）、PDE2A蛋白表达和cGMP水解酶活性持续降低约50%。因此，HET小鼠中的环核苷酸水平显著升高，但出乎意料的是，cGMP的平均百分比变化更高，为153.23%，而cAMP的平均百分比变化更低，为16.41%。因此，为了解释cGMP相对于cAMP的优势增加，我们评估了与PDE2A功能相关的其他磷酸二酯酶。令人惊讶的是，结果相当矛盾：在HET小鼠中，另一种双特异性酶PDE3A和PDE10A的蛋白水平降低，而选择性水解cGMP的PDE5A和PDE9A的表达增加。因此，我们研究了神经元型一氧化氮合酶（nNOS）表达的参与情况，其作为NO/cGMP信号可能增加合成的决定因素。有趣的是，通过蛋白质印迹法和免疫组织化学测量，HET小鼠脑中nNOS的表达水平显著增加，特别是在纹状体的中间神经元中。总之，PDE2A的缺乏可能通过上调nNOS/NO/cGMP途径在纹状体中得到补偿，这反过来可能上调PDE2A依赖的cAMP水解。纹状体nNOS上调与HET小鼠探索行为增加的行为表型之间的神经解剖学相关性得到了进一步研究。
