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Down Syndrome: Toward Optimal Synaptic Function and Cognition


February 13 -15, 2005
Washington, D.C.

Workshop Report

Down Syndrome (DS) is the most common genetic cause of mental retardation, occurring in 1 in 800 live births. DS patients suffer not only cognitive deficits, but also early onset Alzheimer's disease (AD), facial dysmorphology, and increased frequencies of congenital heart disease, gastrointestinal anomalies, and leukemia. Nevertheless, the life expectancy of DS individuals has improved greatly in the past 30 years, to an average of more than 50 years. As the life expectancy of DS individuals increases, their intellectual disabilities and early onset dementia pose increasing personal and societal burdens.

Despite the prevalence of DS, relatively little research has been devoted to understanding the biology of this syndrome, or to developing therapeutics. This neglect has been due in part to the presumed global nature of the molecular and cellular abnormalities in DS: the syndrome is caused by trisomy for chromosome 21, and hence involves misexpression of hundreds of genes. Recent work in mouse models of Down syndrome suggests that there are a variety mechanisms of gene action behind the multitude of phenotypic effects of trisomy 21; for some phenotypes, a very few individual genes on chromosome 21 may be particularly critical. In addition, specific synaptic defects have now been identified in mouse models of DS that appear to be amenable to pharmacological correction. The goal of this workshop was to review recent advances in DS research and relevant technical approaches to identify key priority areas for future work. The invited participants included not only leaders in the field of DS research, but also basic neuroscientists not currently working on DS whose future involvement might help propel the field.

Overview of Cognitive Deficits in Down Syndrome

There is a specific pattern of cognitive deficits in Down Syndrome (DS) which differs from that seen in other mental retardation syndromes (such as Fragile X or Williams Syndrome). People with DS have relatively high levels of social intelligence, but are impaired in expressive communication and explicit memory. Sleep problems are also frequent and may exacerbate the memory problems. Interestingly, the cognitive functions most affected are subserved by structures that mature relatively late in development, such as the prefrontal cortex, hippocampus, and cerebellum.

In addition to the defects in cognitive development that become evident early in life, another major feature of DS is an early onset dementia of the Alzheimer's type. Many patients start showing symptoms of Alzheimer's by early middle age and few are spared completely. It is unclear to what extent the processes underlying the development of the dementia overlap with those responsible for the defects seen in cognitive development. There is also a mysterious variability in the age of onset of dementia in DS: some patients start showing signs in their early 40's, while others appear unaffected even in their 60's and 70's. The genetic factors responsible for the variable penetrance of the dementia phenotype have not yet been explored, but could prove highly informative about the biology of both DS and AD.

Recommendations:

  • More precisely catalog the cognitive deficits that occur in DS, through neuropsychological testing and functional imaging, and in both children and adults. This effort would enable identification of circuits that might be targeted for eventual therapeutics, as well as identify key deficits for study in animal models.
  • Create a DNA repository for patients with DS to enable genotype/phenotype analyses on (1) the nature and severity of cognitive deficits, and (2) the age of onset and severity of dementia.

Synapse formation and structure

A number of developmental abnormalities have been described in the brains of individuals with DS. By 18 months postnatally abnormalities in the development of dendritic spines are seen: spine density is decreased, and spines that are either larger or thinner than normal have been reported. Dendritic abnormalities are also seen in mice that model DS, where increases in spine size are seen throughout the brain and a decrease in spine density is seen in the hippocampus. Such abnormalities are consistent with the memory deficits seen in human DS, and with abnormalities in synaptic plasticity (i.e., long-term potentiation) seen in DS model mice. A number of synaptic proteins may be up- or down-regulated in DS syndrome that are critical to normal spine development and synapse formation.

A key unanswered question is whether defects in synaptic development are initiators of the development of the DS cognitive phenotype, or whether they are a secondary consequence of other, possibly earlier problems in development. For example, it could be that global changes in circuit activity lead to synaptic abnormalities rather than vice versa. And there is some evidence of abnormalities occurring earlier in development, prior to synaptogenesis. For example, reduced neuron numbers (of cerebellar granule cells and cortical interneurons) have been observed during fetal development in humans, and in mouse models there are abnormalities in the timing of neuronal cell birth in the cortex, and in the development of thalamocortical axons. Hence, it will be important to determine the precise sequence of developmental abnormalities that occur in this syndrome.

Recommendations:

  • Undertake a systematic analysis of the development of key structures in the brains of people with DS using standardized techniques and measurements.
  • Understand the sequence of developmental events leading to the abnormal spine phenotype in mouse models of DS, and pursue the underlying genetic and cellular mechanisms.
  • Deploy studies in additional organisms such as C. elegans and Drosophila in which individual chromosome 21 genes can be perturbed, and the effects on the differentiation and maturation of individual neurons and synapses readily studied.

Protein, RNA, and vesicle trafficking

A wealth of information is now available concerning the mechanisms and molecules involved in synaptic vesicle trafficking at the synapse. Several key molecules involved in this process lie on chromosome 21, suggesting plausible hypotheses about how gene dosage might cause deficits in trafficking, spine morphology, and synaptic transmission. Moreoever, enlarged endosomes constitute one of the earliest pathological hallmarks of DS in humans (appearing at 28 weeks of gestation); they are also seen in the Ts65Dn mouse model of DS. However, there is currently little information concerning the level of expression and activity of trafficking proteins in human DS tissue or mouse models, nor functional measures of trafficking in either case.

Because many of its component proteins are known, the synaptic vesicle trafficking system is a good candidate focus system for analyzing the functional impact of chromosome triplication on a specific biological output. This system would also allow one to analyze how the overexpression of a particular gene affects the expression of other genes within the same molecular pathway.

Recommendations

  • Develop direct tests of the hypothesis that synaptic vesicle trafficking is disrupted in DS, including the use of banked human cells and mouse models.
  • Extend the analysis to an assessment of endocytosis and endosomal trafficking, again using both human and mouse tissue
  • Develop panels of mice (or other model organisms) in which genes on chromosome 21 whose proteins are involved in vesicle trafficking and endocytosis are systematically overexpressed, and analyze effects on trafficking, synaptic function, and the expression of other trafficking proteins.

Synapse function

It seems highly likely that the neurophysiological, neuroanatomical, and cognitive deficits seen in DS are accompanied (if not caused by) defects in transmission at individual synapses. Interestingly, studies in the Ts65Dn mouse have shown a defect in long-term potentiation (LTP) at hippocampal synapses. LTP in turn has been postulated to underlie memory formation, which is known to be impaired in DS. However, we have little direct evidence about the nature of the synaptic defects in human DS. Identifying specific synaptic dysfunctions in DS will be key to (1) generating better mouse models, and (2) developing simple in vitro assay systems to test therapeutics.

Other major gap areas include the lack of a current consensus about what behavioral phenotypes one would want to see in a mouse model of DS in order to deem it a "good" model. In addition, nothing is currently known about what synaptic defects may exist in the Ts65Dn mouse outside of the hippocampus. Hence, it would desirable to do a systematic survey of other major brain areas to obtain a more global picture of synaptic function in these animals. (A key step toward this goal would be to develop standardized functional assay methods to enable comparison of results from different labs.) Finally, a major obstacle to further progress has been the difficulty in obtaining reasonable quantities of mice for experiments. The most widely used and best characterized mouse model for DS is the Ts65Dn line. This line is difficult to breed and expensive to obtain, with mice costing $250 a pair. The high cost of mice, and the difficulty in accessing adequate numbers, is limiting research progress.

Recommendations

  • Characterize cognitive deficits in current mouse models to determine which mouse models best mimic the human disease. This endeavor should include input from psychologists/psychiatrists familiar with behavioral and cognitive deficits in human DS.
  • Survey synaptic deficits in DS model mice and determine which ones appear most closely associated with specific cognitive deficits, and which would be best for genotype/phenotype and therapeutics screening purposes.
  • Make existing mouse models available in larger numbers and at reduced cost.
  • Generate additional model mice, and perform genotype/phenotype analyses for cognitive and synaptic abnormalities.
  • Develop standardized methods for testing synaptic and cognitive function in DS model mice.

APP Processing and Transport

Amyloid plaques (which contain A?, a fragment of the APP protein) are seen in the brains of patients with DS, and look identical to those in AD. A similar mechanism may direct the production and deposition of A? in DS and AD. Thus, therapeutics aimed at AD could well be effective in DS as well. Amyloid deposition in AD is known to be due to defects in APP processing and transport. APP processing defects are also likely to play a role in DS, as both APP and one of its processing enzymes (BACE 2) are located on chromosome 21. Indeed, one can readily conceive of means by which misprocessing and/or mistrafficking of APP in DS recreates the pathological changes evident in AD. However, while the biochemistry of APP processing in AD has been studied extensively, relatively little is known about the details of APP biochemistry in DS or the consequences for neuronal function of overexpression and the possible misprocessing and mistrafficking of APP.

Mitochondrial dysfunction is believed to contribute to amyloid deposition in AD. DS patients and model mice exhibit defects in mitochondrial function, some of which have been directly demonstrated to cause abnormalities in APP processing similar to those seen in DS. Thus, improvement of mitochondrial function appears to be another key therapeutic goal.

Recommendations

  • Use amyloid imaging technique to analyze more carefully the earliest stages of amyloid plaque formation in patients with DS and establish more precisely the target time window for early therapeutics and further investigation of pathobiology.
  • Establish cellular locations of defects in APP processing and trafficking and the consequences of such defects for neuronal development and maintenance.
  • Investigate intensively the biochemistry of APP processing in human with DS and in animal models, including mechanisms of APP trafficking and amyloid beta production, degradation and clearance
  • More fully describe the defects in mitochondrial function in DS, and begin developing targeted therapeutics in vitro or in mouse models.
  • Encourage the inclusion of patients with DS in clinical trials of potential AD therapeutics.

From synapse to cognition and behavior

Studies of cognition in DS suggest selective impairment of functions subserved by the hippocampus, prefrontal cortex, and cerebellum. Of these, hippocampal functions appear most profoundly impaired, suggesting that the hippocampus would be a good focus area for future work correlating genetic, cellular, and behavioral deficits. Hippocampal functions that have been demonstrated to be impaired in DS include exploration, context learning, and spatial cognition. Paradoxically, specific measures and testing regimens for these domains have been developed and validated far more extensively in animal models than in humans, especially children.

A great deal of variability is seen in cognitive function among DS patients. Understanding the genetic and environmental factors underlying this variability could be key to improving function for those individuals at the lower end of the spectrum. For example, educational measures seem a promising area. However, we currently know little (from the neuroscience and cognition perspectives) about how education operates on "normal" young minds, much less the minds of children with DS Syndrome. Another gap area is understanding cognitive function and development in individuals with DS at very young ages, from birth to 5 years or so.

Finally, most mechanistic studies of DS have been oriented at exploring the cellular and molecular pathobiology based on known functions of chromosome 21 genes or anatomical abnormalities seen in humans. Another approach would be to do drug screening studies on cognitive function in animal models such as Drosophila or mouse, and let the results of those inform mechanistic studies.

  • Develop better measures of hippocampal function in humans with DS.
  • Develop cognitive batteries that could be used across the life span, and use them to explore the developmental and age-related progression of DS.
  • Link these observations with studies of cognition in mouse models of DS.
  • Distinguish region-specific versus global impairments in neural function.
  • Ascertain whether or not synaptic dysfunction is linked to abnormal cognition.
  • Connect cellular mechanisms and genetic factors to synaptic and cognitive phenotypes
  • Explore the genetic and environmental determinants of variability of cognitive function in DS patients.
  • Develop collaborations with educators, neuropharmacologists, and members of the pharmaceutical industry to begin testing educational and pharmacological interventions.

Overall Recommendations

In addition to specific recommendations listed above, several key focus areas emerged that pertained across all topics:

  • Eliminate barriers to progress and communication
    • Establish an inter-institute working group at NIH to define near- and long-term objectives for the field, identify infrastructure needs, and promote sharing of animal models and reagents.
    • Develop collaborations with educators and members of the pharmaceutical industry to explore potential interventions
    • Raise the consciousness of the neuroscience community to DS as a research topic with the hope of attracting new investigators to field (for example, by developing a symposium at the Society for Neuroscience meeting).
  • Model development:
    • Carry out descriptive studies in parallel in humans and mice to define anatomical, synaptic functional, and cognitive phenotypes over the lifespan, and understand how they are correlated.
    • Identify a few well-defined phenotypes to focus on for further study that can be clearly linked to cognitive deficits seen in human DS, and develop standardized assays for these. The hippocampus seems a reasonable area to focus on in this regard; human studies suggest that prefrontal cortex and cerebellum should also be further explored.
    • Develop standardized assays for synaptic and cognitive function in DS patients and animal models.
  • Resource development
    • Establish a national patient registry
      • Well-characterized cohort of patients for genotype-phenotype investigations (~1000 patients).
      • Couple with DNA database
    • Establish a DS brain bank, cell line repository, and DNA repository
    • Increase supply of old and new mouse models and of needed reagents (and promote sharing among new and established researchers)
    • Support database development
  • Prepare for clinical trials of promising treatments


DOWN SYNDROME: TOWARD OPTIMAL SYNAPTIC FUNCTION AND COGNITION

February 13 - 15, 2004
Willard Hotel
Washington, DC

February 13

6:00-8:00 PM
Reception

Welcome: Story Landis

Opening remarks from co-chairs: Gabrielle Leblanc and Bill Mobley

Keynote talk: Don Price, "Down Syndrome and Models: New Opportunities for Understanding the Neurobiology of the Disease"

February 14

8:30 AM
Presentation: Overview of cognitive deficits in Down Syndrome: Nadel, Silva, and Lott
8:45 AM
Session 1: Synapse formation and structure: Garner, Stein
10:15 AM
Break
10:30 AM
Session 2: RNA and protein trafficking: DiPaolo, Bassell
Noon
Lunch on your own
1:30 PM
Session 3: Synapse function: Malenka, Sudhof
3:00 PM
Break
3:30 PM
Session 4: APP, axonal transport, and synaptic maintenance: Busciglio, Lee
6:30 PM
Dinner

Presentations from advocates:
Madeleine Will (National Down Syndrome Society)
Hollye Doane (Down Syndrome Research and Treatment Foundation)
Lloyd Lewis (patient advocate)

Kathleen Gardiner: Down Syndrome Database

February 15

9:00 AM
Session 5: From synapse to cognition and behavior: Nadel, Silva
10:30 AM
Break
10:45 AM
Session 6: Recommendations for going forward: Mobley, Lott
Noon
Adjourn

Gary J. Bassell, Ph.D.
Associate Professor
Department of Neuroscience
Albert Einstein College of Medicine

Pavel V. Belichenko, M.D., Ph.D.
Basic Life Scientist
Department of Neurology and Neurological Sciences
Stanford University

Jorge Busciglio, Ph.D.
Department of Neurobiology and Behavior
University of California at Irvine

Aiwu Cheng, Ph.D.
Gerontology Research Center
Department of Neuroscience
5600 Nathan Shock Drive
Baltimore, MD 21224
Phone: (410) 558-8465
E-mail: chengai@grc.nia.nih.gov

Carol A. Colton, Ph.D.
Professor
Department of Neurology
Duke University Medical Center

Muriel Davisson, Ph.D.
Senior Staff Scientist
The Jackson Laboratory

Pietro De Camilli, M.D.
Eugene Higgins Professor of Cell Biology
Department of Cell Biology
Yale University

Gilbert DiPaolo, Ph.D.
Assistant Professor
Department of Pathology
College of Physicians and Surgeons
Columbia University Medical Center

Hollye Doane, J.D.
Executive Director
Down Syndrome Research and Treatment Foundation

Lynn E. Dobrunz, Ph.D.
Assistant Professor
Department of Neurobiology
University of Alabama at Birmingham

Jose A. Esteban, Ph.D.
Assistant Professor
Department of Pharmacology
University of Michigan

Zygmunt Galdzicki, Ph.D.
Associate Professor
Department or Anatomy, Physiology and Genetics
USUHS School of Medicine

Katheleen Gardiner, Ph.D.
Professor
Eleanor Roosevelt Institute
University of Denver

Craig C. Garner, Ph.D.
Department of Psychiatric and Behavioral Science

Richard Haier, M.D., Ph.D.
Professor
School of Medicine, Pediatrics
University of California, Irvine

Tarik Haydar, Ph.D.
Assistant Professor
Children's National Medical Center
Children's Research Institute
Center for Neuroscience Research

Joshua Kaplan, Ph.D.
Professor of Genetics
Department of Molecular Biology, Wellman 8
Massachusetts General Hospital
Harvard Medical School

Julie R. Korenberg, M.D., Ph.D.
Cedar Sinai Medical Center
Medical Genetics

Bruce K. Krueger, Ph.D.
Professor
Department of Physiology
University of Maryland School of Medicine

Virginia Lee, Ph.D.
Department of Pathology and Laboratory Medicine
University of Pennsylvania School of Medicine

Lloyd Lewis, M.B.A.
Patient Advocate

Ira Lott, M.D.
Professor and Associate Dean
Department of Child Neurology/Pediatrics
University of California, Irvine
Irvine Medical Center

Myra Madnick, M.Ed.
Executive Director
National Down Sydrome Society

Robert Malenka, M.D., Ph.D.
Pritzher Professor of Psychiatry and Behavioral Sciences
Department of Psychiatary
Stanford University School of Medicine

Sean Millard, Ph.D.
Postdoctoral Fellow
Department of Biological Chemistry
University of California at Los Angeles
Howard Hughed Medical Institute
675 Charles E. Young Drive South
Los Angeles, CA 90095
Phone: (310) 206-3750
Fax: (310) 206-3800
E-mail: smillard@mednet.ucla.edu

William C. Mobley, M.D., Ph.D.
Professor and Chair
Department of Neurology and Neurological Sciences
Stanford University

Lynn Nadel, Ph.D.
Regent's Professor of Psychology
College of Social and Behavioral Sciences
University of Arizona

Cristopher Niell
Department of Molecular and Cell Physiology
Stanford University

Ralph A. Nixon, M.D., Ph.D.
Professor and Director
Department of Psychiatary and Cell Biology
New York University School of Medicine

David Patterson, Ph.D.
Director/Professor
Department of Biological Sciences
University of Denver
Eleanor Roosevelt Institute

Donald L. Price, M.D., Ph.D.
Professor of Pathology, Neurology and Neuroscience
Department of Pathology, Division of Neuropathology
Johns Hopkins University School of Medicine

Roger Reeves, Ph.D.
Professor
Department of Physiology and Institute of Genetic Medicine
Johns Hopkins University School of Medicine/p>

Alcino Jose Silva, Ph.D.
Professor
Departments of Neurobiology, Psychiatry and Psychology
University of California at Los Angeles

Elke Stein, Ph.D.
Assistant Professor
Department MCDB and Cell Biology
Yale University

Thomas C. Sudhof, M.D.
Professor
Center for Basic Neuroscience
University of Texas Southwestern Medical Center at Dallas
Howard Hughes Medical Institute

Madeleine Will
Director
National Policy Center
National Down Sydrome Society

NIH Staff

Neil Buckholtz, Ph.D.
Chief, Dementias of Aging Branch
Neuroscience and Neuropsychology of Aging Program
National Institute on Aging
National Institutes of Health
7201 Wisconsin Avenue, Suite 350
fBethesda, MD 20892
Phone: (301) 496-9350
Fax: (301) 496-1494
E-mail: buckholn@nia.nih.gov

Karen Chang, Ph.D.
Postdoctoral Fellow
Neurogentics
National Institute of Neurological Disorders and Stroke
National Institutes of Health
9000 Rockville Pike, MSC-3705
Building 35, Room 2A1006
Bethesda, MD 20892
Phone: (301) 402-7365
Fax: (301) 480-3365
E-mail: changk@ninds.nih.gov

A. Ray Chaudhuri, Ph.D., M.B.A.
Program Analyst, Neurogenetics
National Institute of Neurological Disorders and Stroke
National Institutes of Health
6001 Executive Boulevard
Rockville, MD 20892
Phone: (301) 496-5745
Fax (301) 402-1501
E-mail: chaudhuri@ninds.nih.gov

Emmeline Edwards, Ph.D.
Acting Deputy Director for Extramural
Research Program Director for Systems and Cognitive Neuroscience
National Institute of Neurological Disorders and Stroke
National Institutes of Health
6001 Executve Boulevard, Room 3305
Bethesda, MD 20892
Phone: (301) 496-9248
E-mail: ee48r@nih.gov

Katrina Gwinn-Hardy, Ph.D.
Program Director
Neurogenetics
National Institute of Neurological Disorders and Stroke
National Institutes of Health
6001 Executive Boulevard, Room 2136
Rockville, MD 20852
Phone: (301) 496-5745
Fax: (301) 402-1501
E-mail: gwinnk@ninds.nih.gov

Story Landis, Ph.D.
National Institute of Neurological Disorders and Stroke
National Institutes of Health
Building 31, Room 8A52
Bethesda, MD 20892
Phone: (301) 946-9746
E-mail: landiss@ninds.nih.gov

Gabrielle G. Leblanc, Ph.D.
Program Director
Neurogenetics
National Institute of Neurological Disorders and Stroke
National Institutes of Health
6001 Executive Boulevard, Suite 2136
Bethesda, MD 20892
Phone: (301) 496-5745
Fax: (301) 402-1501
E-mail: leblancg@ninds.nih.gov

Kyung-Tai Min, Ph.D.
Principal Investigator
Neurogenetics Branch
National Institute of Neurological Disorders and Stroke
National Institutes of Health
9000 Rockville Pike, MSC-3705
Building 35, Room 2A1002
Bethesda, MD 20892
Phone: (301) 402-7353
Fax: (301) 480-3365
E-mail: mink@mail.nih.gov

Mary Lou OsterGranite, Ph.D.
National Institute of Child Health and Development
6100/4B09
Bethesda, MD 20892
Phone: (301) 435-6866
E-mail: granitem@mail.nih.gov

Quandra Scudder
Program Analyst, Neurogenetics
National Institute of Neurological Disorders and Stroke
National Institutes of Health
6001 Executive Boulevard
Rockville, MD 20892
Phone: (301) 496-5745
Fax (301) 402-1501
E-mail: scudderq@nih.gov

D. Stephen Snyder, Ph.D.
Etiology of Alzheimer's Disease
Neuroscience and Neuropsychology of Aging
National Institute on Aging
National Institutes of Health
Gateway Building, Room 350
7201 Wisconsin Avenue, MSC-9205
Bethesda, MD 20892-9205
Phone: (301) 496-9350 or (301) 594-7664
Fax: (301) 496-1494
E-mail: ss82f@nih.gov or Stephen.Snyder@nih.hhs.gov

Danilo Tagle, Ph.D.
National Institute of Neurological Disorders and Stroke
National Institutes of Health
Neuroscience Center Building, Room 2133
Bethesda, MD 20892
Phone: (301) 496-5745
Fax: (301) 402-1501
E-mail: tagle@ninds.nih.gov

Ljubisa Vitkovic, Ph.D.
Mental Retardation and Developmental Disabilities Branch
Center for Developmental Biology and Perinatal Medicine
National Institute for Child Health and Human Development
National Institutes of Health
Room 4B09E, MSC-7510
6100 Executive Boulevard
Bethesda, MD 20892
Phone: (301) 402-1822
Fax: (301) 496-3791
E-mail: vitkovil@mail.nih.gov

Last updated March 10, 2011