title: Select 3',5'-cyclic nucleotide phosphodiesterases exhibit altered expression in the aged rodent brain.
abstract: 3',5'-cyclic nucleotide phosphodiesterases (PDEs) are the only known enzymes to compartmentalize cAMP and cGMP, yet little is known about how PDEs are dynamically regulated across the lifespan. We mapped mRNA expression of all 21 PDE isoforms in the adult rat and mouse central nervous system (CNS) using quantitative polymerase chain reaction (qPCR) and in situ hybridization to assess conservation across species. We also compared PDE mRNA and protein in the brains of old (26 months) versus young (5 months) Sprague-Dawley rats, with select experiments replicated in old (9 months) versus young (2 months) BALB/cJ mice. We show that each PDE isoform exhibits a unique expression pattern across the brain that is highly conserved between rats, mice, and humans. PDE1B, PDE1C, PDE2A, PDE4A, PDE4D, PDE5A, PDE7A, PDE8A, PDE8B, PDE10A, and PDE11A showed an age-related increase or decrease in mRNA expression in at least 1 of the 4 brain regions examined (hippocampus, cortex, striatum, and cerebellum). In contrast, mRNA expression of PDE1A, PDE3A, PDE3B, PDE4B, PDE7A, PDE7B, and PDE9A did not change with age. Age-related increases in PDE11A4, PDE8A3, PDE8A4/5, and PDE1C1 protein expression were confirmed in hippocampus of old versus young rodents, as were age-related increases in PDE8A3 protein expression in the striatum. Age-related changes in PDE expression appear to have functional consequences as, relative to young rats, the hippocampi of old rats demonstrated strikingly decreased phosphorylation of GluR1, CaMKIIα, and CaMKIIβ, decreased expression of the transmembrane AMPA regulatory proteins γ2 (a.k.a. stargazin) and γ8, and increased trimethylation of H3K27. Interestingly, expression of PDE11A4, PDE8A4/5, PDE8A3, and PDE1C1 correlate with these functional endpoints in young but not old rats, suggesting that aging is not only associated with a change in PDE expression but also a change in PDE compartmentalization.
authors.affiliation: University of South Carolina School of Medicine, Department of Pharmacology, Physiology & Neuroscience, 6439 Garners Ferry Rd, Columbia, SC 29209, USA. Electronic address: Michy.Kelly@uscmed.sc.edu.
authors.forename: Michy P
authors.initials: MP
authors.lastname: Kelly
authors.affiliation: Pfizer Global Research and Development, Neuroscience Research Unit, Eastern point Road, Groton, CT 06340, USA. Electronic address: w.adamowicz@kolltan.com.
authors.forename: Wendy
authors.initials: W
authors.lastname: Adamowicz
authors.affiliation: Pfizer Global Research and Development, Neuroscience Research Unit, Eastern point Road, Groton, CT 06340, USA. Electronic address: susanebove@gmail.com.
authors.forename: Susan
authors.initials: S
authors.lastname: Bove
authors.affiliation: University of South Carolina School of Medicine, Department of Pharmacology, Physiology & Neuroscience, 6439 Garners Ferry Rd, Columbia, SC 29209, USA.
authors.forename: Alexander J
authors.initials: AJ
authors.lastname: Hartman
authors.affiliation: Pfizer Global Research and Development, Neuroscience Research Unit, Eastern point Road, Groton, CT 06340, USA. Electronic address: Abigail.Mariga@med.nyu.edu.
authors.forename: Abigail
authors.initials: A
authors.lastname: Mariga
authors.affiliation: University of South Carolina School of Medicine, Department of Pharmacology, Physiology & Neuroscience, 6439 Garners Ferry Rd, Columbia, SC 29209, USA.
authors.forename: Geetanjali
authors.initials: G
authors.lastname: Pathak
authors.affiliation: Pfizer Global Research and Development, Neuroscience Research Unit, Eastern point Road, Groton, CT 06340, USA.
authors.forename: Veronica
authors.initials: V
authors.lastname: Reinhart
authors.affiliation: Pfizer Global Research and Development, Neuroscience Research Unit, Eastern point Road, Groton, CT 06340, USA. Electronic address: aromegialli@student.uchc.edu.
authors.forename: Alison
authors.initials: A
authors.lastname: Romegialli
authors.affiliation: Pfizer Global Research and Development, Neuroscience Research Unit, Eastern point Road, Groton, CT 06340, USA. Electronic address: Robin.Kleiman@childrens.harvard.edu.
authors.forename: Robin J
authors.initials: RJ
authors.lastname: Kleiman
mesh_terms: D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000235:genetics / Q000378:metabolism*; D000375:Aging; D000818:Animals; D001921:Brain / Q000201:enzymology* / Q000378:metabolism; D002531:Cerebellum / Q000201:enzymology / Q000378:metabolism; D002540:Cerebral Cortex / Q000201:enzymology / Q000378:metabolism; D003342:Corpus Striatum / Q000201:enzymology / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D006624:Hippocampus / Q000201:enzymology / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D020033:Protein Isoforms; D012333:RNA, Messenger; D015105:3',5'-Cyclic-AMP Phosphodiesterases
keywords: Alzheimer's disease; Model; Neuron; PDE11; PDE8; Tissue distribution