Cyclic GMP-mediated memory enhancement in the object recognition test by inhibitors of phosphodiesterase-2 in mice

Lindsay M. Lueptow

doi:10.1007/s00213-015-4129-1

Cyclic GMP-mediated memory enhancement in the object recognition test by inhibitors of phosphodiesterase-2 in mice

2015-11-02

37

PRE

AI

L

Lindsay M. Lueptow *

C

Chang‐Guo Zhan

J

James M. O’Donnell

DOI：10.1007/s00213-015-4129-1

Original

Original request for help

Save

Abstract

En 中文

Rationale and objectives Cyclic nucleotide phosphodiesterase2 (PDE2) is a potential therapeutic target for the treatment of cognitive dysfunction. Using the object recognition test (ORT), this study assessed the effects of two PDE2 inhibitors, Bay 60-7550 and ND7001, on learning and memory, and examined underlying mechanisms. Methods To assess the role of PDE2 inhibition on phases of memory, Bay 60-7550 (3 mg/kg) was administered: 30 min prior to training; 0, 1, or 3 h after training; or 30 min prior to recall testing. To assess cyclic nucleotide involvement in PDE2 inhibitor-enhanced memory consolidation, either the nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME; 20 mg/kg; intraperitoneal (IP)), soluble guanylyl cyclase inhibitor 1H-[-1,2,4] oxadiazolo-[4,3-a] quinoxalin-1-one (ODQ; 20 mg/kg; IP), protein kinase G inhibitor KT5823 (2.5 mu g; intracerebroventricular (ICV)), or protein kinase A inhibitor H89 (1 mu g; ICV) was administered 30 min prior to the PDE2 inhibitor Bay 60-7550 (3 mg/kg) or ND7001 (3 mg/kg). Changes in the phosphorylation of 3'5'-cyclic adenosine monophosphate (cAMP) response element binding protein (CREB) at Ser-133 and vasodilatorstimulated phosphoprotein (VASP) at Ser-239 were determined to confirm activation of cAMP and 3' 5'-cyclic guanosine monophosphate (cGMP) signaling. Results Bay 60-7550 (3 mg/kg) enhanced memory of mice in the ORT when given 30 min prior to training, immediately after training, or 30 min prior to recall. Inhibitors of the cGMP pathway blocked the memory-enhancing effects of both Bay 60-7550 (3 mg/kg) and ND7001 (3 mg/kg) on early consolidation processes. Bay 60-7550 (3 mg/kg) enhanced phosphorylation of CREB and VASP, both targets of cGMP-dependent protein kinase (PKG). Conclusions These results confirm a potential of PDE2, or components of its signaling pathway, as a therapeutic target for drug discovery focused on restoring memory function.

Keywords:

Cognition

Learning and memory

Phosphodiesterase inhibitors

Phosphodiesterase-2

Object recognition test

Cyclic GMP

Cyclic AMP

Nitric oxide synthase

Protein kinase G

Soluble guanylyl cyclase

Cyclic GMP-mediated memory enhancement in the object recognition test by inhibitors of phosphodiesterase-2 in mice

Abstract

Journal

Organization