title: Phosphodiesterase 11A in brain is enriched in ventral hippocampus and deletion causes psychiatric disease-related phenotypes.
abstract: Phosphodiesterase 11A (PDE11A) is the most recently identified family of phosphodiesterases (PDEs), the only known enzymes to break down cyclic nucleotides. The tissue expression profile of this dual specificity PDE is controversial, and little is understood of its biological function, particularly in the brain. We seek here to determine if PDE11A is expressed in the brain and to understand its function, using PDE11A(-/-) knockout (KO) mice. We show that PDE11A mRNA and protein are largely restricted to hippocampus CA1, subiculum, and the amygdalohippocampal area, with a two- to threefold enrichment in the ventral vs. dorsal hippocampus, equal distribution between cytosolic and membrane fractions, and increasing levels of protein expression from postnatal day 7 through adulthood. Interestingly, PDE11A KO mice show subtle psychiatric-disease-related deficits, including hyperactivity in an open field, increased sensitivity to the glutamate N-methyl-D-aspartate receptor antagonist MK-801, as well as deficits in social behaviors (social odor recognition memory and social avoidance). In addition, PDE11A KO mice show enlarged lateral ventricles and increased activity in CA1 (as per increased Arc mRNA), phenotypes associated with psychiatric disease. The increased sensitivity to MK-801 exhibited by PDE11A KO mice may be explained by the biochemical dysregulation observed around the glutamate alpha-amino-3-hydroxy-5-methyl-4-isozazolepropionic (AMPA) receptor, including decreased levels of phosphorylated-GluR1 at Ser845 and the prototypical transmembrane AMPA-receptor-associated proteins stargazin (gamma2) and gamma8. Together, our data provide convincing evidence that PDE11A expression is restricted in the brain but plays a significant role in regulating brain function.
authors.affiliation: Pfizer Research, Princeton, NJ 08852, USA. michele.kelly@pfizer.com
authors.forename: Michele P
authors.initials: MP
authors.lastname: Kelly
authors.forename: Sheree F
authors.initials: SF
authors.lastname: Logue
authors.forename: Julie
authors.initials: J
authors.lastname: Brennan
authors.forename: Jonathon P
authors.initials: JP
authors.lastname: Day
authors.forename: Subha
authors.initials: S
authors.lastname: Lakkaraju
authors.forename: Lixin
authors.initials: L
authors.lastname: Jiang
authors.forename: Xiaotian
authors.initials: X
authors.lastname: Zhong
authors.forename: May
authors.initials: M
authors.lastname: Tam
authors.forename: Stacey J
authors.initials: SJ
authors.lastname: Sukoff Rizzo
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Platt
authors.forename: Jason M
authors.initials: JM
authors.lastname: Dwyer
authors.forename: Sarah
authors.initials: S
authors.lastname: Neal
authors.forename: Virginia L
authors.initials: VL
authors.lastname: Pulito
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Agostino
authors.forename: Steven M
authors.initials: SM
authors.lastname: Grauer
authors.forename: Rachel L
authors.initials: RL
authors.lastname: Navarra
authors.forename: Cody
authors.initials: C
authors.lastname: Kelley
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Comery
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Murrills
authors.forename: Miles D
authors.initials: MD
authors.lastname: Houslay
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Brandon
mesh_terms: D015106:3',5'-Cyclic-GMP Phosphodiesterases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001522:Behavior, Animal; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D005973:Glutamine / Q000378:metabolism; D006624:Hippocampus / Q000201:enzymology* / Q000473:pathology; D008297:Male; D001523:Mental Disorders / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010641:Phenotype; D012333:RNA, Messenger / Q000235:genetics; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction; D012919:Social Behavior
chemical_list: D012333:RNA, Messenger; D016194:Receptors, N-Methyl-D-Aspartate; D005973:Glutamine; D015106:3',5'-Cyclic-GMP Phosphodiesterases; C520793:Pde11a protein, mouse
references.citation: Neuropharmacology. 2008 Jun;54(7):1136-42
references.pmid: 18423777
references.citation: Proc Natl Acad Sci U S A. 1998 Dec 8;95(25):15020-5
references.pmid: 9844008
references.citation: J Biol Chem. 2000 Oct 6;275(40):31469-79
references.pmid: 10906126
references.citation: Neuropsychopharmacology. 2002 Oct;27(4):587-95
references.pmid: 12377395
references.citation: Behav Brain Res. 2009 Dec 7;204(2):295-305
references.pmid: 19100784
references.citation: Mol Psychiatry. 2008 Jun;13(6):631-40
references.pmid: 17684498
references.citation: Neuropsychopharmacology. 2008 Jun;33(7):1611-23
references.pmid: 17700644
references.citation: Proc Natl Acad Sci U S A. 2000 Mar 28;97(7):3702-7
references.pmid: 10725373
references.citation: Proc Natl Acad Sci U S A. 2000 Nov 7;97(23):12891-5
references.pmid: 11050148
references.citation: Neuron. 2009 Jan 15;61(1):101-12
references.pmid: 19146816
references.citation: J Neurosci. 2008 Dec 17;28(51):13952-6
references.pmid: 19091983
references.citation: Psychopharmacology (Berl). 2008 Mar;197(1):115-26
references.pmid: 18060387
references.citation: Neuropharmacology. 2007 Jul;53(1):113-24
references.pmid: 17559891
references.citation: Brain Res Bull. 2003 Sep 30;61(5):489-95
references.pmid: 13679247
references.citation: Biochemistry. 2007 Sep 11;46(36):10353-64
references.pmid: 17696499
references.citation: Pharmacol Biochem Behav. 2009 Jun;92(4):649-54
references.pmid: 19303035
references.citation: J Pharmacol Exp Ther. 2008 Aug;326(2):369-79
references.pmid: 18456873
references.citation: Int J Impot Res. 2005 May-Jun;17(3):216-23
references.pmid: 15800654
references.citation: Neuropharmacology. 2006 Aug;51(2):386-96
references.pmid: 16780899
references.citation: Neuropharmacology. 2006 Aug;51(2):374-85
references.pmid: 16769090
references.citation: Psychopharmacology (Berl). 2005 May;179(3):613-9
references.pmid: 15672274
references.citation: Neuroscience. 2007 Jan 5;144(1):239-46
references.pmid: 17081698
references.citation: Biol Psychiatry. 2008 Feb 15;63(4):349-52
references.pmid: 17643398
references.citation: Mol Psychiatry. 2009 Apr;14(4):398-415, 347
references.pmid: 19030002
references.citation: Pharmacol Rev. 2006 Sep;58(3):488-520
references.pmid: 16968949
references.citation: Arch Gen Psychiatry. 2009 Sep;66(9):938-46
references.pmid: 19736350
references.citation: Curr Drug Targets. 2007 May;8(5):583-602
references.pmid: 17504103
references.citation: Trends Neurosci. 2008 May;31(5):234-42
references.pmid: 18395805
references.citation: Annu Rev Biochem. 2007;76:481-511
references.pmid: 17376027
references.citation: Biol Psychiatry. 2006 Mar 1;59(5):415-23
references.pmid: 16199013
references.citation: Pharmacol Biochem Behav. 1999 May;63(1):185-92
references.pmid: 10340540
references.citation: J Pharmacol Exp Ther. 2008 May;325(2):681-90
references.pmid: 18287214
references.citation: Learn Mem. 2008 Jan 28;15(2):75-83
references.pmid: 18230676
references.citation: Eur J Pharmacol. 2007 Mar 8;558(1-3):107-12
references.pmid: 17207788
references.citation: Eur J Biochem. 2001 Aug;268(16):4440-8
references.pmid: 11502204
references.citation: Cancer Res. 2006 Dec 15;66(24):11571-5
references.pmid: 17178847
references.citation: Psychopharmacology (Berl). 2009 May;204(1):37-48
references.pmid: 19107466
references.citation: Schizophr Res. 2001 Apr 15;49(1-2):1-52
references.pmid: 11343862
references.citation: Prog Neurobiol. 2003 Jul;70(4):319-45
references.pmid: 12963091
references.citation: Neuropsychopharmacology. 2007 Mar;32(3):577-88
references.pmid: 16738544
references.citation: Science. 2005 Nov 18;310(5751):1187-91
references.pmid: 16293762
references.citation: J Pharmacol Exp Ther. 2009 Nov;331(2):574-90
references.pmid: 19661377
references.citation: Proc Natl Acad Sci U S A. 2006 Oct 10;103(41):15124-9
references.pmid: 17008408
references.citation: Psychopharmacol Bull. 2003 Spring;37(2):79-101
references.pmid: 14566217
references.citation: Eur J Biochem. 2001 Jan;268(1):168-78
references.pmid: 11121118
references.citation: Drug Discov Today. 2005 Nov 15;10(22):1503-19
references.pmid: 16257373
references.citation: J Neurosci. 2007 Aug 29;27(35):9513-24
references.pmid: 17728464
references.citation: J Histochem Cytochem. 2005 Jul;53(7):895-903
references.pmid: 15995148
references.citation: Neurobiol Learn Mem. 2002 Sep;78(2):470-6
references.pmid: 12431431