Phosphodiesterase Targets for Cognitive Dysfunction and Schizophrenia
Posted May 04, 2010
Schizophrenia is a debilitating psychiatric disease that involves three symptomatic domains: "positive" symptoms such as hallucinations and delusions, "negative" symptoms like anhedonia and blunted speech, and cognitive deficits in attention, memory, and other higher functions. The "classical hypothesis" of schizophrenia holds that excess dopamine neurotransmission in subcortical regions is responsible for positive symptoms. An alternate hypothesis emphasizes hypofunction of the NMDA receptor, part of the glutamate signaling system, in accounting for all symptom domains. Both of these neurotransmitters activate second messenger systems in their signal transduction cascades.
Many second messenger systems depend upon cyclic nucleotide signaling, which thereby plays an important role in neuronal signal transduction and neuronal plasticity. In this system, cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP), are inactivated by cyclic nucleotide phosphodiesterase (PDE) enzymes, which break the phosphodiester bond in cAMP or cGMP. Interfering with PDEs is one way to modulate the activity of the neurotransmitter; thus PDEs represent a potential target for treating symptom domains in schizophrenia.
The state of the art in phosphodiesterase inhibition was the focus of the January 26, 2010, meeting of the Biochemical Pharmacology Discussion Group, held at the New York Academy of Sciences. The meeting surveyed what is currently understood about the biology and function of PDEs in relation to psychiatric disease and cognitive enhancement, and offered detailed portraits of some of the members of this large and complex family of enzymes.
Use the tabs above to find a meeting report and multimedia from this event.
Presentations are available from:
Joseph A. Beavo (University of Washington)
Richard Keefe (Duke University Medical Center)
Jos Prickaerts (Maastricht University)
Ted Abel (University of Pennsylvania)
Hanting Zhang (West Virginia University Health Sciences Center)
Laboratory and Company Sites with Background Information and Research Results
News and background information on the research programs at Intra-Cellular Therapies includes a discussion of the treatment needs in schizophrenia.
Beavo JA, Francis SH, Houslay MD. 2006. Cyclic Nucleotide Phosphodiesterases in Health and Disease. CRC Press, Boca Raton, FL.
Keefe RSE, Eesley CE. 2009. Neurocognition of Schizophrenia. In Sadock BJ, Sadock VA, Ruiz P, eds. Kaplan and Sadock's Comprehensive Textbook of Psychiatry. 9th edition. Lippincott Williams & Wilkins, Philadelphia, PA.
Kelly MP, Isiegas C, Cheung YF, et al. 2007. Constitutive activation of Galphas within forebrain neurons causes deficits in sensorimotor gating because of PKA-dependent decreases in cAMP. Neuropsychopharmacology 32: 577-588. Full Text
Kelly MP, Stein JM, Vecsey CG, et al. 2009. Developmental etiology for neuroanatomical and cognitive deficits in mice overexpressing Galphas, a G-protein subunit genetically linked to schizophrenia. Mol. Psychiatry 14: 398-415, 347.
Vecsey CG, Baillie GS, Jaganath D, et al. 2009. Sleep deprivation impairs cAMP signalling in the hippocampus. Nature 461: 1122-1125. Full Text
Bender AT, Beavo JA. 2006. Cyclic nucleotide phosphodiesterases: molecular regulation to clinical use. Pharmacol. Rev 58: 488-520. Full Text
Charych EI, Liu F, Moss SJ, Brandon NJ. 2009. GABA(A) receptors and their associated proteins: implications in the etiology and treatment of schizophrenia and related disorders. Neuropharmacology 57: 481-495.
Grauer SM, Pulito VL, Navarra RL, et al. 2009. Phosphodiesterase 10A inhibitor activity in preclinical models of the positive, cognitive, and negative symptoms of schizophrenia. J. Pharmacol. Exp. Ther. 331: 574-590.
Hertz AL, Bender AT, Smith KC, et al. 2009. Elevated cyclic AMP and PDE4 inhibition induce chemokine expression in human monocyte-derived macrophages. Proc. Natl. Acad. Sci. USA 106: 21978-21983.
Surapisitchat J, Jeon KI, Yan C, Beavo JA. 2007. Differential regulation of endothelial cell permeability by cGMP via phosphodiesterases 2 and 3. Circ. Res. 101: 811-818. Full Text
Buchanan RW, Keefe RSE, Umbricht D, et al. 2010. The FDA-NIMH-MATRICS guidelines for clinical trial design of cognitive-enhancing drugs: What do we know 5 years later? Schiz. Bull. April 21 (Epub ahead of print).
Keefe RSE, Harvey PD. 2008. Implementation considerations for multi-site clinical trials with cognitive neuroscience tasks. Schiz. Bull. 34: 656-663. Full Text
Keefe RSE, Bilder RM, Davis SM, et al. 2007. Neurocognitive effects of antipsychotic medications in patients with chronic schizophrenia in the CATIE trial. Arch. Gen. Psychiatry 64: 633-647. Full Text
Reichenberg A, Caspi A, Harrington H, et al. 2010. Static and dynamic cognitive deficits in childhood preceding adult schizophrenia: a 30-year study. Am. J. Psychiatry 167: 160-169.
Robin J. Kleiman
Coskran TM, Morton D, Menniti FS, et al. 2006. Immunohistochemical localization of phosphodiesterase 10A in multiple mammalian species. J. Histochem Cytochem. 54: 1205-1213. Full Text
Threlfell S, Sammut S, Menniti FS, et al. 2009. Inhibition of Phosphodiesterase 10A Increases the Responsiveness of Striatal Projection Neurons to Cortical Stimulation. J. Pharmacol. Exp. Ther. 328: 785-795. Full Text
Xie Z, Adamowicz WO, Eldred WD, et al. 2006. Cellular and subcellular localization of PDE10A, a striatum-enriched phosphodiesterase. Neuroscience 139: 597-607. Full Text
Reneerkens OA, Rutten K, Steinbusch HW, et al. 2009. Selective phosphodiesterase inhibitors: a promising target for cognition enhancement. Psychopharmacology (Berl) 202: 419-443. Full Text
Rutten K, Basile JL, Prickaerts J, et al. 2008. Selective PDE inhibitors rolipram and sildenafil improve object retrieval performance in adult cynomolgus macaques. Psychopharmacology (Berl) 196: 643-648. Full Text
Rutten K, Van Donkelaar EL, Ferrington L, et al. 2009. Phosphodiesterase inhibitors enhance object memory independent of cerebral blood flow and glucose utilization in rats. Neuropsychopharmacology 34: 1914-1925.
Li YF, Huang Y, Amsdell SL, et al. 2009. Antidepressant- and anxiolytic-like effects of the phosphodiesterase-4 (PDE4) inhibitor rolipram on behavior depend on cyclic AMP-response element binding protein (CREB)-mediated neurogenesis in the hippocampus. Neuropsychopharmacology 34: 2404-2419. Full Text
Zhang HT. 2009. Cyclic AMP-specific phosphodiesterase-4 as a target for the development of antidepressant drugs. Curr. Pharm. Des. 15: 1688-1698.
Zhang HT, Crissman AM, Dorairaj NR, et al. 2000. Inhibition of cyclic AMP phosphodiesterase (PDE4) reverses memory deficits associated with NMDA receptor antagonism. Neuropsychopharmacology 23: 198-204. (PDF, 196 KB) Full Text
Zhang HT, Huang Y, Masood A, et al. 2008. Anxiogenic-like behavioral phenotype of mice deficient in phosphodiesterase 4B (PDE4B). Neuropsychopharmacology 33: 1611-1623. (PDF, 296 KB) Full Text
Zhang HT, Huang Y, Jin SLC, et al. 2002. Antidepressant-like profile and reduced sensitivity to rolipram in mice deficient in the PDE4D phosphodiesterase enzyme. Neuropsychopharmacology 27: 587-595. (PDF, 177 KB) Full Text
Lawrence P. Wennogle, PhD
Lawrence Wennogle supervises Intra-Cellular Therapies (ITI) development of small molecule therapeutics for neurodegenerative and neuropsychiatric disorders. Wennogle received his PhD in Biochemistry from the University of Colorado, Boulder. Working under Howard Berg and Marvin Caruthers, he studied the structure of red blood cell membranes. He then completed two postdoctoral positions, one at the University of Colorado and the second at the Pasteur Institute in Paris, France, working under Jean-Pierre Changeux on the structure-function of the nicotinic acetylcholine receptor for Torpedo marmorata.
For the past 29 years, Wennogle has been involved in the research and development in the pharmaceutical industry. He was a staff scientist and principal research fellow at Ciba-Geigy and Novartis for 19 years, where he led drug discovery programs for CNS disorders, cardiovascular disease, diabetes and inflammation. Included in his experiences while at Novartis, he served on an "Expert Committee in Molecular Biology" with world-wide responsibility to evaluate new technologies.
Wennogle is a fellow of the New York Academy of Sciences and has co-authored over 45 scientific publications. He is a member of the New York Academy of Sciences, the American Association for the Advancement of Science, and the Society for Neurosciences. He has adjunct appointments at Columbia University in the Department of Pharmacology and at University of Medicine and Dentistry, New Jersey in the Graduate School of Biomedical Sciences. His current focus is the development of novel therapeutics for cognitive dysfunction.
Peter Hutson, PhD
Merck and Co., Inc.
Peter Hutson is currently the head of the Psychiatry Research department, Merck and Co. Inc., and is focused on the development of novel therapeutics for schizophrenia and depression. Hutson received his PhD in pharmacology from the Institute of Neurology, University of London where he studied the role of stress and 5-HT1A presynaptic autoreceptors on the regulation of brain serotonin function. He subsequently joined the Neuroscience Research Centre, Merck Sharp and Dohme in the UK and led drug development and research programs for CNS disorders. He is a member of the Society for Neuroscience and European College of Neuropsychopharmacology and has co-authored over 50 scientific publications.
Ted Abel, PhD
Ted Abel is the Edmund J. and Louise W. Kahn Term Professor of Biology and Director of the Biological Basis of Behavior Program at the University of Pennsylvania. He also directs an NIMH Graduate Training Program in Behavioral and Cognitive Neuroscience at Penn. Abel was an undergraduate at Swarthmore College, receiving a BA in Chemistry in 1985. After Swarthmore, Abel attended the University of Cambridge (Christ's College) as a Marshall Scholar, receiving an M. Phil. in Biochemistry and working with R. Tim Hunt on the cloning of cyclin. Abel then moved to Harvard University to work with Tom Maniatis on transcriptional regulation during Drosophila development. After receiving his PhD in Biochemistry and Molecular Biology in 1993 from Harvard University, Abel moved to the College of Physicians and Surgeons at Columbia University to do his postdoctoral work with Eric Kandel. There he worked on genetic approaches to study the role of protein kinase A in neuronal function.
In 1998, Abel joined the Biology Department at the University of Pennsylvania as an assistant professor. His lab focuses on the role of the protein kinase A signaling pathway as well as transcriptional and epigenetic regulation in memory storage, sleep/wake regulation and mouse models of psychiatric disease. Abel has received numerous awards and fellowships including the John Merck Scholars Award, a David and Lucile Packard Fellowship in Science and Engineering, a Young Investigator Award from the Mental Retardation and Developmental Disabilities Research Center at the Children's Hospital of Philadelphia, and the School of Arts and Sciences Dean's Award for Mentorship of Undergraduate Research at Penn. In 2006, Abel was selected as the recipient of the. In 2005, Dr. Abel was elected to membership in the American College of Neuropsychopharmacology.
Abel is an associate editor of Behavioral Neuroscience and a member of the editorial board of Hippocampus. He has been a member of the Scientific Review Council and the Board of Directors of Cure Autism Now, and served on the Scientific Advisory Committee of Autism Speaks. He has served on grant review panels for the National Science Foundation and for the National Institutes of Health (NIH), and he is currently a member of the Learning and Memory Study Section at NIH and the Scientific Advisory Board of Autism Speaks. Abel's research has been supported by grants from the NIH, the David and Lucile Packard Foundation, Human Frontiers Science Program, the Whitehall Foundation and the John Merck Fund.
Joseph A. Beavo, PhD
Joseph Beavo is currently a professor of Pharmacology at the University of Washington. His interests in cyclic nucleotide phosphodiesterases started while a graduate student with Earl Sutherland and Joel Hardman at Vanderbilt University. After several years of work with Edwin Krebs on protein kinases at the University of California, Davis, he returned to studies on phosphodiesterases when he set up his own laboratory in Seattle. He has continued this interest in this area since that time.
Nicholas Brandon, PhD
Nick Brandon is currently the head of Psychiatry Research at Pfizer. Previously he led the Schizophrenia Research group at Wyeth after starting his industry career with Merck at the Neuroscience Research Center in the UK. While at Merck, Brandon's work focused on identifying and validating novel targets and animal models for both schizophrenia and AD. In particular he championed efforts around glutamate-based approaches for schizophrenia.
He has recently spent a lot of time developing PDE inhibitor approaches for the CNS, most notably through interest in PDE10A and PDE4. In addition Brandon has a keen interest in the role of risk genes and related pathways in setting up and driving disease processes and the related pathology, as exemplified through efforts around understanding the function of the risk gene Disrupted in Schizophrenia 1 (DISC1). In addition he has been very interested in the role of synapses and how they go wrong in disease and the possible approaches to rectify such deficits, as exemplified by work on estrogen.
Brandon was educated at Pembroke College Cambridge and did his PhD with Stephen Moss at University College London on the regulation of GABAA receptors. After postdoctoral training in London he moved to Merck directly. He has published approximately 50 articles.
Richard Keefe, PhD
Richard Keefe is a professor of Psychiatry & Behavioral Sciences and Psychology at Duke University Medical Center (Durham, NC). His team within Duke University is primarily devoted to understanding cognitive dysfunction in patients with schizophrenia and related disorders. It has led the development of the battery of tests for several multi-site studies of cognitive dysfunction treatment-response, including the National Institute of Mental Health (NIMH) Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) and the Brief Assessment of Cognition in Schizophrenia (BACS), a battery of tests that can be used in clinical trials or clinical settings to assess cognitive deficit treatment response.
Keefe has been involved in several pharmacologic trials for improving cognition in schizophrenia, including a recently begun a pilot study to determine if computer-based cognitive remediation intervention is feasible and effective in a multi-site context. His group at Duke is also collaborating with the Institute of Mental Health in Singapore to complete a proof-of-concept study of the effects of pregnenolone on cognition in schizophrenia, and to investigate the cognitive and neuroanatomical factors that may predict the conversion to psychosis in young people at high risk. This project will test the hypothesis that psychosis is precipitated by impairments in memory-dependent perceptual processes.
Robin J. Kleiman, PhD
Robin Kleiman received her PhD in Neuroscience from the University of Virginia. Her thesis work focused on understanding mechanisms of dendritic RNA sorting and transport in cultured neurons. Her postdoctoral work at the University of California, San Francisco, examined receptor tyrosine kinase signal transduction, neurite outgrowth, and neurotrophin-induced synaptic plasticity at the neuromuscular junction.
Kleiman joined the CNS Discovery Biology group at Pfizer, Inc. in 1999. Kleiman began working with the CNS phosphodiesterase group in 2001 and has developed an interest in the role that this class of enzymes may play in neurodegenerative and psychiatric diseases, with a particular emphasis on the biology of PDE9 and PDE2. Her laboratory has also been involved in pathway-based identification of new drug targets including the use of imaging platforms for phenotypic screening and expression profiling for the characterization of target biology and the processes that underlie synaptic plasticity.
Jos Prickaerts, PhD
Jos Prickaerts is a neurobiologist who received his PhD degree in 1998 in Memory Formation and Drugs at the Department of Psychiatry and Neuropsychology at Maastricht University. Until 2004 he worked as a postdoc in multidisciplinary teams at both Maastricht University and in the pharmaceutical industry (e.g., Johnson and Johnson PRD, Belgium).
Since 2004 he has been an assistant professor working in both the Department of Psychiatry and Neuropsychology (Faculty of Health, Medicine and Life Sciences) and the Department of Neuropsychology and Psychopharmacology (Faculty of Psychology and Neurosciences) at Maastricht University. His research group focuses on signal transduction and plasticity in affective disorders and cognitive processes. In particular the role of growth factors and phosphodiesterases is being studied. His research involves working with animal models and tests in a translational context.
Hanting Zhang, MD, PhD
Hanting Zhang is an assistant professor of Behavioral Medicine & Psychiatry and Pharmacology at West Virginia University School of Medicine. He studies the roles of phosphodiesterases (PDEs) in intracellular signaling in the mediation of memory, depression, anxiety, and Alzheimer's disease.
Zhang was granted NARSAD Young Investigator Awards from the U.S. Mental Health Association in 2006 and 2008. He was the chair of the "Phosphodiesterases in the CNS" session at the international Gordon Research Conference on PDEs (Barga, Italy) and the honored speaker at Beijing University of Chinese Medicine supported by the Ministry of Education, China, both in 2008. He has published more than 30 papers in peer-reviewed journals and 14 review articles and book chapters.
Kathleen McGowan is a freelance magazine writer specializing in science and medicine.