Phosphodiesterase-1b (Pde1b) knockout mice are resistant to forced swim and tail suspension induced immobility and show upregulation of Pde10a.
BACKGROUND
Major depressive disorder is a leading cause of suicide and disability. Despite this, current antidepressants provide insufficient efficacy in more than 60% of patients. Most current antidepressants are presynaptic reuptake inhibitors; postsynaptic signal regulation has not received as much attention as potential treatment targets.


OBJECTIVE
We examined the effects of disruption of the postsynaptic cyclic nucleotide hydrolyzing enzyme, phosphodiesterase (PDE) 1b, on depressive-like behavior and the effects on PDE1B protein in wild-type (WT) mice following stress.


METHODS
Littermate knockout (KO) and WT mice were tested in locomotor activity, tail suspension (TST), and forced swim tests (FST). FST was also used to compare the effects of two antidepressants, fluoxetine and bupropion, in KO versus WT mice. Messenger RNA (mRNA) expression changes were also determined. WT mice underwent acute or chronic stress and markers of stress and PDE1B expression were examined.


RESULTS
Pde1b KO mice exhibited decreased TST and FST immobility. When treated with antidepressants, both WT and KO mice showed decreased FST immobility and the effect was additive in KO mice. Mice lacking Pde1b had increased striatal Pde10a mRNA expression. In WT mice, acute and chronic stress upregulated PDE1B expression while PDE10A expression was downregulated after chronic but not acute stress.


CONCLUSIONS
PDE1B is a potential therapeutic target for depression treatment because of the antidepressant-like phenotype seen in Pde1b KO mice.
Division of Neurology (MLC 7044), Department of Pediatrics, Cincinnati Children's Research Foundation and University of Cincinnati College of Medicine, 3333 Burnet Ave., Cincinnati, OH, USA.
Jillian R
JR
Hufgard
Division of Neurology (MLC 7044), Department of Pediatrics, Cincinnati Children's Research Foundation and University of Cincinnati College of Medicine, 3333 Burnet Ave., Cincinnati, OH, USA.
Michael T
MT
Williams
Division of Neurology (MLC 7044), Department of Pediatrics, Cincinnati Children's Research Foundation and University of Cincinnati College of Medicine, 3333 Burnet Ave., Cincinnati, OH, USA.
Matthew R
MR
Skelton
Neuroscience Research Division, Lilly Research Centre, Eli Lilly & Co. Ltd., Windlesham, Surrey, UK.
Olivera
O
Grubisha
Neuroscience Research Division, Lilly Research Centre, Eli Lilly & Co. Ltd., Windlesham, Surrey, UK.
Filipa M
FM
Ferreira
Neuroscience Research Division, Lilly Research Centre, Eli Lilly & Co. Ltd., Windlesham, Surrey, UK.
Helen
H
Sanger
Department of Biology, Mount Saint Joseph University, Cincinnati, OH, 45233, USA.
Mary E
ME
Wright
Department of Biology, Mount Saint Joseph University, Cincinnati, OH, 45233, USA.
Tracy M
TM
Reed-Kessler
Lilly Corporate Center, Lilly Research Laboratories, Indianapolis, IN, 46285, USA.
Kurt
K
Rasmussen
Department of Psychiatry, Yale University School of Medicine, 34 Park St., New Haven, CT, 06519-1109, USA.
Ronald S
RS
Duman
Division of Neurology (MLC 7044), Department of Pediatrics, Cincinnati Children's Research Foundation and University of Cincinnati College of Medicine, 3333 Burnet Ave., Cincinnati, OH, USA. charles.vorhees@cchmc.org.
Charles V
CV
Vorhees
D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology / Q000627:therapeutic use; D003342:Corpus Striatum / Q000187:drug effects / Q000201:enzymology; D054677:Cyclic Nucleotide Phosphodiesterases, Type 1 / Q000172:deficiency*; D003863:Depression / Q000188:drug therapy / Q000201:enzymology; D005260:Female; D019417:Hindlimb Suspension / Q000379:methods / Q000523:psychology*; D007103:Immobilization / Q000379:methods / Q000523:psychology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010727:Phosphoric Diester Hydrolases / Q000096:biosynthesis*; D013550:Swimming / Q000523:psychology*; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology*
D000928:Antidepressive Agents; C492284:Pde10a protein, mouse; D010727:Phosphoric Diester Hydrolases; D054677:Cyclic Nucleotide Phosphodiesterases, Type 1; C517267:Pde1b protein, mouse
Forced swim test; PDE1B; Pde brain gene expression; Pde1b knockout mice; Phosphodiesterase; Stress resistance