Phosphodiesterase 11A in brain is enriched in ventral hippocampus and deletion causes psychiatric disease-related phenotypes

Kelly, M. P. et al. (2010) Phosphodiesterase 11A in brain is enriched in ventral hippocampus and deletion causes psychiatric disease-related phenotypes. Proceedings of the National Academy of Sciences of the United States of America, 107(18), pp. 8457-8462. (doi:10.1073/pnas.1000730107)

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Publisher's URL: http://dx.doi.org/10.1073/pnas.1000730107

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 (gamma 2) and gamma 8. Together, our data provide convincing evidence that PDE11A expression is restricted in the brain but plays a significant role in regulating brain function.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Houslay, Professor Miles and Day, Dr Jonathan and Brandon, Dr Nicholas
Authors: Kelly, M. P., Logue, S. F., Brennan, J., Day, J. P., Lakkaraju, S., Jiang, L., Zhong, X., Tam, M., Sukoff Rizzo, S. J., Platt, B. J., Dwyer, J. M., Neal, S., Pulito, V. L., Agostino, M. J., Grauer, S. M., Navarra, R. L., Kelley, C., Comery, T. A., Murrills, R. J., Houslay, M. D., and Brandon, N. J.
Subjects:R Medicine > RC Internal medicine > RC0321 Neuroscience. Biological psychiatry. Neuropsychiatry
College/School:College of Medical Veterinary and Life Sciences > Institute of Neuroscience and Psychology
Journal Name:Proceedings of the National Academy of Sciences of the United States of America
Publisher:National Academy of Sciences
ISSN:0027-8424
ISSN (Online):1091-6490
Published Online:19 April 2010
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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
432501Transatlantic networks of excellence in cardiovascular diseaseMiles HouslayFoundation Leducq (LEDUCQ-VIL)06 CVD 02Institute of Neuroscience and Psychology
438301Phosphodiesterase-4 isoforms - intracellular targeting, regulation and potential therapeutic targetsMiles HouslayMedical Research Council (MRC)G0600765Institute of Neuroscience and Psychology