Haploinsufficiency of PDE2A causes in mice increased exploratory behavior associated with upregulation of neural nitric oxide synthase in the striatum
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...
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Elsevier
2025-02-01
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| Series: | Neurobiology of Disease |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0969996124003838 |
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| author | Ana Gabriela de Oliveira do Rêgo Francesca D'Amico Vincenza D’Angelo Silvia Cardarelli Debora Cutuli Davide Decandia Eugenia Landolfo Laura Petrosini Manuela Pellegrini Marcello D’Amelio Nicola Biagio Mercuri Mauro Giorgi Giuseppe Sancesario |
| author_facet | Ana Gabriela de Oliveira do Rêgo Francesca D'Amico Vincenza D’Angelo Silvia Cardarelli Debora Cutuli Davide Decandia Eugenia Landolfo Laura Petrosini Manuela Pellegrini Marcello D’Amelio Nicola Biagio Mercuri Mauro Giorgi Giuseppe Sancesario |
| author_sort | Ana Gabriela de Oliveira do Rêgo |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-c799a03265ce488db91a1ef5b03bbc91 |
| institution | Kabale University |
| issn | 1095-953X |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neurobiology of Disease |
| spelling | doaj-art-c799a03265ce488db91a1ef5b03bbc912025-01-24T04:44:39ZengElsevierNeurobiology of Disease1095-953X2025-02-01205106781Haploinsufficiency of PDE2A causes in mice increased exploratory behavior associated with upregulation of neural nitric oxide synthase in the striatumAna Gabriela de Oliveira do Rêgo0Francesca D'Amico1Vincenza D’Angelo2Silvia Cardarelli3Debora Cutuli4Davide Decandia5Eugenia Landolfo6Laura Petrosini7Manuela Pellegrini8Marcello D’Amelio9Nicola Biagio Mercuri10Mauro Giorgi11Giuseppe Sancesario12Department of Biology and Biotechnology “Charles Darwin”, Sapienza University, 00185 Rome, ItalyDepartment of Biology and Biotechnology “Charles Darwin”, Sapienza University, 00185 Rome, ItalyDepartment of Systems Medicine, Tor Vergata University, 00133 Rome, ItalyDepartment of Biology and Biotechnology “Charles Darwin”, Sapienza University, 00185 Rome, ItalyIRCCS Santa Lucia Foundation, 00179 Rome, Italy; Department of Psychology, Sapienza University, 00185 Rome, ItalyIRCCS Santa Lucia Foundation, 00179 Rome, Italy; Department of Psychology, Sapienza University, 00185 Rome, ItalyIRCCS Santa Lucia Foundation, 00179 Rome, ItalyIRCCS Santa Lucia Foundation, 00179 Rome, ItalyInstitute of Biochemistry and Cell Biology, IBBC-CNR, 00015 Monterotondo Scalo, Rome, ItalyIRCCS Santa Lucia Foundation, 00179 Rome, Italy; Department of Medicine, Campus Biomedico University, 00128 Rome, ItalyDepartment of Systems Medicine, Tor Vergata University, 00133 Rome, Italy; IRCCS Santa Lucia Foundation, 00179 Rome, ItalyDepartment of Biology and Biotechnology “Charles Darwin”, Sapienza University, 00185 Rome, Italy; Corresponding author.Department of Systems Medicine, Tor Vergata University, 00133 Rome, ItalyPhosphodiesterase 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.http://www.sciencedirect.com/science/article/pii/S0969996124003838Phosphodiesterase 2APDE2A heterozygous +/− micecAMPcGMPPDE3PDE5 |
| spellingShingle | Ana Gabriela de Oliveira do Rêgo Francesca D'Amico Vincenza D’Angelo Silvia Cardarelli Debora Cutuli Davide Decandia Eugenia Landolfo Laura Petrosini Manuela Pellegrini Marcello D’Amelio Nicola Biagio Mercuri Mauro Giorgi Giuseppe Sancesario Haploinsufficiency of PDE2A causes in mice increased exploratory behavior associated with upregulation of neural nitric oxide synthase in the striatum Neurobiology of Disease Phosphodiesterase 2A PDE2A heterozygous +/− mice cAMP cGMP PDE3 PDE5 |
| title | Haploinsufficiency of PDE2A causes in mice increased exploratory behavior associated with upregulation of neural nitric oxide synthase in the striatum |
| title_full | Haploinsufficiency of PDE2A causes in mice increased exploratory behavior associated with upregulation of neural nitric oxide synthase in the striatum |
| title_fullStr | Haploinsufficiency of PDE2A causes in mice increased exploratory behavior associated with upregulation of neural nitric oxide synthase in the striatum |
| title_full_unstemmed | Haploinsufficiency of PDE2A causes in mice increased exploratory behavior associated with upregulation of neural nitric oxide synthase in the striatum |
| title_short | Haploinsufficiency of PDE2A causes in mice increased exploratory behavior associated with upregulation of neural nitric oxide synthase in the striatum |
| title_sort | haploinsufficiency of pde2a causes in mice increased exploratory behavior associated with upregulation of neural nitric oxide synthase in the striatum |
| topic | Phosphodiesterase 2A PDE2A heterozygous +/− mice cAMP cGMP PDE3 PDE5 |
| url | http://www.sciencedirect.com/science/article/pii/S0969996124003838 |
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