Inhibition of phosphodiesterase 2 increases neuronal cGMP, synaptic plasticity and memory performance.
An essential element of the signalling cascade leading to synaptic plasticity is the intracellular second messenger molecule guanosine 3',5'-cyclic monophosphate (cGMP). Using the novel, potent, and selective inhibitor Bay 60-7550, we show that the enzyme 3',5'-cyclic nucleotide phosphodiesterase type 2 (PDE2) is responsible for the degradation of newly synthesized cGMP in cultured neurons and hippocampal slices. Inhibition of PDE2 enhanced long-term potentiation of synaptic transmission without altering basal synaptic transmission. Inhibition of PDE2 also improved the performance of rats in social and object recognition memory tasks, and reversed MK801-induced deficits in spontaneous alternation in mice in a T-maze. Our data provide strong evidence that inhibition of PDE2 can improve memory functions by enhancing neuronal plasticity.
Boess
Frank G
FG
Bayer Healthcare AG, Pharma Research CNS, 42096 Wuppertal-Elberfeld, Germany.
Hendrix
Martin
M
van der Staay
Franz-Josef
FJ
Erb
Christina
C
Schreiber
Rudy
R
van Staveren
Wilma
W
de Vente
Jan
J
Prickaerts
Jos
J
Blokland
Arjan
A
Koenig
Gerhard
G
D000818:Animals; D016466:CHO Cells; D002417:Cattle; D006224:Cricetinae; D000242:Cyclic AMP / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism*; D005092:Exonucleases / Q000037:antagonists & inhibitors*; D006168:Guinea Pigs; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D017774:Long-Term Potentiation / Q000187:drug effects; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008568:Memory / Q000187:drug effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D009473:Neuronal Plasticity / Q000187:drug effects*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D011597:Psychomotor Performance / Q000187:drug effects*; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins; D015398:Signal Transduction / Q000187:drug effects
D010726:Phosphodiesterase Inhibitors; D011994:Recombinant Proteins; D000242:Cyclic AMP; D005092:Exonucleases; C022650:spleen exonuclease; D006152:Cyclic GMP