Phosphodiesterase 11A in brain is enriched in ventral hippocampus and deletion causes psychiatric disease-related phenotypes.
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.
Kelly
Michele P
MP
Pfizer Research, Princeton, NJ 08852, USA. michele.kelly@pfizer.com
Logue
Sheree F
SF
Brennan
Julie
J
Day
Jonathon P
JP
Lakkaraju
Subha
S
Jiang
Lixin
L
Zhong
Xiaotian
X
Tam
May
M
Sukoff Rizzo
Stacey J
SJ
Platt
Brian J
BJ
Dwyer
Jason M
JM
Neal
Sarah
S
Pulito
Virginia L
VL
Agostino
Michael J
MJ
Grauer
Steven M
SM
Navarra
Rachel L
RL
Kelley
Cody
C
Comery
Thomas A
TA
Murrills
Richard J
RJ
Houslay
Miles D
MD
Brandon
Nicholas J
NJ
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
D012333:RNA, Messenger; D016194:Receptors, N-Methyl-D-Aspartate; D005973:Glutamine; D015106:3',5'-Cyclic-GMP Phosphodiesterases; C520793:Pde11a protein, mouse
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