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Phosphodiesterase-4D knock-out and RNA interference-mediated knock-down enhance memory and increase hippocampal neurogenesis via increased cAMP signaling.
J Neurosci. 2011 Jan 05; 31(1):172-83.JN

Abstract

Phosphodiesterase-4 (PDE4) plays an important role in mediating memory via the control of intracellular cAMP signaling; inhibition of PDE4 enhances memory. However, development of PDE4 inhibitors as memory enhancers has been hampered by their major side effect of emesis. PDE4 has four subtypes (PDE4A-D) consisting of 25 splice variants. Mice deficient in PDE4D displayed memory enhancement in radial arm maze, water maze, and object recognition tests. These effects were mimicked by repeated treatment with rolipram in wild-type mice. In addition, similarly as rolipram-treated wild-type mice, PDE4D-deficient mice also displayed increased hippocampal neurogenesis and phosphorylated cAMP response element-binding protein (pCREB). Furthermore, microinfusion of lentiviral vectors that contained microRNAs (miRNAs) targeting long-form PDE4D isoforms into bilateral dentate gyri of the mouse hippocampus downregulated PDE4D4 and PDE4D5, enhanced memory, and increased hippocampal neurogenesis and pCREB. Finally, while rolipram and PDE4D deficiency shortened α2 adrenergic receptor-mediated anesthesia, a surrogate measure of emesis, miRNA-mediated PDE4D knock-down in the hippocampus did not. The present results suggest that PDE4D, in particular long-form PDE4D, plays a critical role in the mediation of memory and hippocampal neurogenesis, which are mediated by cAMP/CREB signaling; reduced expression of PDE4D, or at least PDE4D4 and PDE4D5, in the hippocampus enhances memory but appears not to cause emesis. These novel findings will aid in the development of PDE4 subtype- or variant-selective inhibitors for treatment of disorders involving impaired cognition, including Alzheimer's disease.

Authors+Show Affiliations

Department of Behavioral Medicine and Psychiatry, West Virginia University Health Sciences Center, Morgantown, West Virginia 26506, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

21209202

Citation

Li, Yun-Feng, et al. "Phosphodiesterase-4D Knock-out and RNA Interference-mediated Knock-down Enhance Memory and Increase Hippocampal Neurogenesis Via Increased cAMP Signaling." The Journal of Neuroscience : the Official Journal of the Society for Neuroscience, vol. 31, no. 1, 2011, pp. 172-83.
Li YF, Cheng YF, Huang Y, et al. Phosphodiesterase-4D knock-out and RNA interference-mediated knock-down enhance memory and increase hippocampal neurogenesis via increased cAMP signaling. J Neurosci. 2011;31(1):172-83.
Li, Y. F., Cheng, Y. F., Huang, Y., Conti, M., Wilson, S. P., O'Donnell, J. M., & Zhang, H. T. (2011). Phosphodiesterase-4D knock-out and RNA interference-mediated knock-down enhance memory and increase hippocampal neurogenesis via increased cAMP signaling. The Journal of Neuroscience : the Official Journal of the Society for Neuroscience, 31(1), 172-83. https://doi.org/10.1523/JNEUROSCI.5236-10.2011
Li YF, et al. Phosphodiesterase-4D Knock-out and RNA Interference-mediated Knock-down Enhance Memory and Increase Hippocampal Neurogenesis Via Increased cAMP Signaling. J Neurosci. 2011 Jan 5;31(1):172-83. PubMed PMID: 21209202.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Phosphodiesterase-4D knock-out and RNA interference-mediated knock-down enhance memory and increase hippocampal neurogenesis via increased cAMP signaling. AU - Li,Yun-Feng, AU - Cheng,Yu-Fang, AU - Huang,Ying, AU - Conti,Marco, AU - Wilson,Steven P, AU - O'Donnell,James M, AU - Zhang,Han-Ting, PY - 2011/1/7/entrez PY - 2011/1/7/pubmed PY - 2011/2/5/medline SP - 172 EP - 83 JF - The Journal of neuroscience : the official journal of the Society for Neuroscience JO - J Neurosci VL - 31 IS - 1 N2 - Phosphodiesterase-4 (PDE4) plays an important role in mediating memory via the control of intracellular cAMP signaling; inhibition of PDE4 enhances memory. However, development of PDE4 inhibitors as memory enhancers has been hampered by their major side effect of emesis. PDE4 has four subtypes (PDE4A-D) consisting of 25 splice variants. Mice deficient in PDE4D displayed memory enhancement in radial arm maze, water maze, and object recognition tests. These effects were mimicked by repeated treatment with rolipram in wild-type mice. In addition, similarly as rolipram-treated wild-type mice, PDE4D-deficient mice also displayed increased hippocampal neurogenesis and phosphorylated cAMP response element-binding protein (pCREB). Furthermore, microinfusion of lentiviral vectors that contained microRNAs (miRNAs) targeting long-form PDE4D isoforms into bilateral dentate gyri of the mouse hippocampus downregulated PDE4D4 and PDE4D5, enhanced memory, and increased hippocampal neurogenesis and pCREB. Finally, while rolipram and PDE4D deficiency shortened α2 adrenergic receptor-mediated anesthesia, a surrogate measure of emesis, miRNA-mediated PDE4D knock-down in the hippocampus did not. The present results suggest that PDE4D, in particular long-form PDE4D, plays a critical role in the mediation of memory and hippocampal neurogenesis, which are mediated by cAMP/CREB signaling; reduced expression of PDE4D, or at least PDE4D4 and PDE4D5, in the hippocampus enhances memory but appears not to cause emesis. These novel findings will aid in the development of PDE4 subtype- or variant-selective inhibitors for treatment of disorders involving impaired cognition, including Alzheimer's disease. SN - 1529-2401 UR - https://www.unboundmedicine.com/medline/citation/21209202/Phosphodiesterase_4D_knock_out_and_RNA_interference_mediated_knock_down_enhance_memory_and_increase_hippocampal_neurogenesis_via_increased_cAMP_signaling_ L2 - http://www.jneurosci.org/cgi/pmidlookup?view=long&pmid=21209202 DB - PRIME DP - Unbound Medicine ER -