Table Of ContentSERIES EDITORS
STEPHEN G. WAXMAN
BridgetMarieFlahertyProfessorofNeurology
Neurobiology,andPharmacology;
Director,CenterforNeuroscience&Regeneration/NeurorehabilitationResearch
YaleUniversitySchoolofMedicine
NewHaven,Connecticut
USA
DONALD G. STEIN
AsaG.CandlerProfessor
DepartmentofEmergencyMedicine
EmoryUniversity
Atlanta,Georgia
USA
DICK F. SWAAB
ProfessorofNeurobiology
MedicalFaculty,UniversityofAmsterdam;
LeaderResearchTeamNeuropsychiatricDisorders
NetherlandsInstituteforNeuroscience
Amsterdam
TheNetherlands
HOWARD L. FIELDS
ProfessorofNeurology
EndowedChairinPharmacologyofAddiction
Director,WheelerCenterfortheNeurobiologyofAddiction
UniversityofCalifornia
SanFrancisco,California
USA
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List of Contributors
S.Abekhoukh,Institute ofMolecularandCellularPharmacology,CNRS-UMR6097,UniversitédeNice
Sophia-Antipolis, Valbonne, France
M.M. Ahmed, Department of Pediatrics, University of Colorado Denver, Denver, CO, USA
X. Altafaj, Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), and
Institute of Neuropathology, IDIBELL, L’Hospitalet de Llobregat, Barcelona, Spain
S.E. Antonarakis, Department of Genetic Medicine and Development, University of Geneva Medical
School, University Hospitals of Geneva, and iGE3 Institute of Genetics and Genomics of Geneva,
Geneva, Switzerland
B. Bardoni, Institute of Molecular and Cellular Pharmacology, CNRS-UMR6097, Université de Nice
Sophia-Antipolis, Valbonne, France
P.V. Belichenko, Department of Neurosciences, and Down Syndrome Center for Research and Treat-
ment, University of California, San Diego, La Jolla, CA, USA
V. Brault, Institut de Génétique et de Biologie Moléculaire et Cellulaire, Translational medicine and
Neurogenetics program, IGBMC, CNRS, INSERM, Université de Strasbourg, UMR7104, UMR964,
Illkirch, Strasbourg, France
D.G. Currier, Department of Physiology, The McKusick-Nathans Institute for Genetic Medicine, Johns
Hopkins University School of Medicine, Baltimore, MA, USA
R. de la Torre, Neurosciences Research Programme, IMIM-Hospital del Mar Research Institute and
CIBEROBN, Barcelona, Spain
M.Dierssen,GenesandDiseaseProgramme,CentredeRegulacióGenómicaandCIBERER,Barcelona,
Spain
A. Duchon, Institut de Génétique et de Biologie Moléculaire et Cellulaire, Translational medicine and
Neurogenetics program, IGBMC, CNRS, INSERM, Université de Strasbourg, UMR7104, UMR964,
Illkirch, Strasbourg, France
J.O. Edgin, University of Arizona, Down Syndrome Research Group, Tucson, AZ, USA
M.Esteller,CancerEpigenetics andBiologyProgram (PEBC),BellvitgeBiomedicalResearchInstitute,
L’Hospitalet, Barcelona, Catalonia, Spain
A. Fernández, University of Arizona, Down Syndrome Research Group, Tucson, AZ, USA
C. Fillat, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), and Centro de
Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Barcelona, Spain
K.J.Gardiner,DepartmentofPediatrics;ComputationalBiosciencesProgram;IntellectualandDevelop-
mental Disabilities Research Center, and Human Medical Genetics and Neuroscience Programs,
University of Colorado Denver, Denver, CO, USA
Y. Herault, Institut de Génétique et de Biologie Moléculaire et Cellulaire, Translational medicine and
Neurogenetics program, IGBMC, CNRS, INSERM, Université de Strasbourg, UMR7104, UMR964;
Transgenèse et Archivage Animaux Modèles, TAAM, CNRS, UPS44, Orléans, and Institut Clinique
de la Souris, ICS, GIE CERBM, Illkirch, Strasbourg, France
v
vi
D.Huertas,CancerEpigeneticsand Biology Program (PEBC),BellvitgeBiomedicalResearch Institute,
L’Hospitalet, Barcelona, Catalonia, Spain
A.M. Kleschevnikov, Department of Neurosciences, and Down Syndrome Center for Research and
Treatment, University of California, San Diego, La Jolla, CA, USA
T. Le, Department of Computer Science and Engineering, University of Colorado Denver, Denver,
CO, USA
A. Letourneau, Department of Genetic Medicine and Development, University of Geneva Medical
School, University Hospitals of Geneva, and iGE3 Institute of Genetics and Genomics of Geneva,
Geneva, Switzerland
J. Levenga, Department of Physiology and Neuroscience, New York University, School of Medicine,
New York, NY, USA
I.T. Lott, Department of Pediatrics and Neurology, School of Medicine, University of California Irvine
(UCI), Orange, CA, USA
D. Maréchal, Institut de Génétique et de Biologie Moléculaire et Cellulaire, Translational medicine and
Neurogenetics program, IGBMC, CNRS, INSERM, Université de Strasbourg, UMR7104, UMR964,
Illkirch, Strasbourg, France
G.M. Mason, University of Arizona, Down Syndrome Research Group, Tucson, AZ, USA
M. Melko, Institute of Molecular and Cellular Pharmacology, CNRS-UMR6097, Université de Nice
Sophia-Antipolis, Valbonne, France
L. Nadel, University of Arizona, Down Syndrome Research Group, Tucson, AZ, USA
R.C. Polk, Department of Physiology, The McKusick-Nathans Institute for Genetic Medicine, Johns
Hopkins University School of Medicine, Baltimore, MA, USA
R.H. Reeves, Department of Physiology, The McKusick-Nathans Institute for Genetic Medicine, Johns
Hopkins University School of Medicine, Baltimore, MA, USA
A. Salehi, VA Palo Alto Health Care System, Palo Alto, and Department of Psychiatry and Behavioral
Sciences, Stanford Medical School, Stanford, CA, USA
J.V. Sanchez-Mut, Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research
Institute, L’Hospitalet, Barcelona, Catalonia, Spain
G. Spanò, University of Arizona, Down Syndrome Research Group, Tucson, AZ, USA
X.Sturgeon,DepartmentofPediatrics,andComputationalBiosciencesProgram,UniversityofColorado
Denver, Denver, CO, USA
E. Velot, Institut de Génétique et de Biologie Moléculaire et Cellulaire, Translational medicine and
Neurogenetics program, IGBMC, CNRS, INSERM, Université de Strasbourg, UMR7104, UMR964,
Illkirch, Strasbourg, France
R. Willemsen, CBG-Department of Clinical Genetics, Erasmus MC, Rotterdam, The Netherlands
C. Wu, Department of Neurosciences, and Down Syndrome Center for Research and Treatment,
University of California, San Diego, La Jolla, CA, USA
S. Zongaro, Institute of Molecular and Cellular Pharmacology, CNRS-UMR6097, Université de Nice
Sophia-Antipolis, Valbonne, France
Preface
Downsyndrome(DS)isthemostcommonexampleofneurogeneticaneuploiddisorderleadingtomental
retardation. In most cases, DS results from an extra copy of chromosome 21 (HSA21) producing
deregulated gene expression in brain that gives rise to suboptimal intellectual functioning. Although
several hypotheses have been put forward, it is unclear as to how candidate gene loci or genomic
elementsonHSA21causeDS-associatedfeatures.DespitetheprevalenceofDS,relativelylittleresearch
has been devoted to understanding its neurobiology or to developing therapeutics for cognitive deficits.
This neglect has been due in part to the presumed global nature of the molecular and cellular
abnormalities in DS that involves misexpression of hundreds of genes. Nevertheless, recent work in
mousemodelssuggeststhatspecificsynapticdefectsleadingtomentalretardationareamenabletophar-
macologicalcorrectionandmaydependonaveryfewcriticalgenesonHSA21.Besides,theunderstand-
ing of the pathogenicity of the extragenomic material in trisomy 21 has been speed up in the past years
due to the recent advances in genome sequencing, comparative genome analysis, functional genome
exploration, and the use ofmodelorganisms. This has ledto newevidence-based approaches to preven-
tion or amelioration of DS effects on the brain and cognition and will impact other research areas on
neurogenomics of cognition and behavior.
This volume focuses on DS as prototype of “genomic disorder.” Exciting new findings demonstrating
considerable plasticity of the human genome are helping to identify how deregulation/dysfunction of a
myriadofdifferentmoleculesinDSaffectcellularmechanismsunderlyingneuronaldevelopment(neurite
outgrowthand neuronalmorphogenesis, shaping the three-dimensional architecture of neurons, synapse
andnetworkformation)and synapse rearrangement,allowinglong-termmemoryformation andadapta-
tion to the environment. Concepts such as metabolome or conectome are certainly important to be
includedaskeysfortheglobalunderstandingofDSandothermentalretardationsyndromes.Theauthors
evaluate and interpret recent progress in the understanding of the role of genome-altering processes in
the generation of mental retardation and neural phenotypes in DS and how does this concept reconcile
with phenotypic variability associated with aneuploidy. We also review the new modeling strategies in
mice and illustrate the potential that genetically engineered mouse models of DS can provide into the
understanding of the molecular biology of human learning disorders and into the development of new
therapies. Moreover, the increase in the life expectancy in DS individuals pose significant personal and
societal burdens, since DS patients suffer early onset Alzheimer’s disease, neurological symptoms.
This book brings together scientists of diverse backgrounds, integrating research directed at different
levelsofbiologicalorganizationandhighlightingtranslationalresearchandtheapplicationoftheexisting
scientific knowledge to develop improved DS treatments and cures. The authors are leaders in the field
of DS clinical, basic neuroscience and neurogenomics, research, representing both basic and clinical
aspects to promote translational aspects. They focus on the recent advances, challenges, and diagnosis/
therapeuticimplicationsof genomicstructural and functionalvariationinbrain systems relatedto cogni-
tion and disease-related dysfunction, focusing on both mouse and human studies.
Mara Dierssen
Rafael de la Torre
vii
M.DierssenandR.delaTorre(Eds.)
ProgressinBrainResearch,Vol.197
ISSN:0079-6123
Copyright(cid:1)2012ElsevierB.V.Allrightsreserved.
CHAPTER1
Therapeutic approaches in the improvement of
cognitive performance in Down syndrome: past,
present, and future
Rafael de la Torre{,* and Mara Dierssen{
{ NeurosciencesResearchProgramme,IMIM-HospitaldelMarResearchInstituteandCIBEROBN,Barcelona,Spain
{ GenesandDisease Programme,CentredeRegulacióGenómicaandCIBERER, Barcelona,Spain
Abstract: Clinical trials with drugs aimed at treatment of Alzheimer disease to decelerate cognitive
decline and translated mimetically to demented and young nondemented Down syndrome patients have
been unable to demonstrate improvements in cognitive performance and functioning. Unfortunately,
results from clinical trials do not support the use of NMDA antagonists like memantine and we should
await at the development of safer GABA(A) antagonists to conclude about the efficacy of approaching
Downsyndrometherapeuticsbymodulatingneurotransmission systems altered inthispathology. Theuse
of folinic acid or antioxidants in DS patients is not supported by scientific evidence and do not provide
improvement in cognitive performance to patients. Alternatively to the modulation of neurotransmission
systems, future therapeutic approaches should focus at normalizing the expression levels or function of
candidate molecules. Epigallocatechin gallate, a green tea polyphenol, that modulates DYRK1A
functioninghasalreadyshownpreliminarilythatthisapproachmayproveusefulintherapeutics.
Keywords: therapeutics; folinic acid; donezepil; rivastagmine; galantamine; vitamins and minerals; ace-
tyl-l-carnitine; epigallocatechin gallate; memantine; DYRK1A; acetylcholinesterase inhibitors; gabaergic
GABA(A) antagonists; N-methyl-d-aspartate (NMDA) antagonists.
Introduction
Downsyndrome(DS)isthemostcommongenetic
cause(trisomyofchromosome21)ofmentalretar-
*Correspondingauthor. dationappearinginabout9.65ofevery10,000live
Tel.:þ34-933-160-484;Fax:þ34-933-160-467
births in the European countries (EUROCAT,
E-mail:[email protected]
DOI:10.1016/B978-0-444-54299-1.00001-7 1
2
2010;Khoshnoodetal.,2011)itischaracterizedbya between25and75islessthanaverage(averagescore
rangeofphysicalandpsychologicalconditions.The inthepopulationissetat100).
increased protein expression of genes on The present chapter will focus at therapies
chromosome21leadstoacascadeofeffectsinthe oriented at improving cognitive performance
developmentoffetalbrainstructureandsubsequent of DS patients nondemented and with preva-
structuralandbehavioraleffectsacrossthelifespan lent Alzheimer’s disease (AD) symptoms (see
of individuals with DS (Lott and Dierssen, 2010). Chapter 6). In Table 1, there is a summary of
Three of the more affected areas are the cerebral the main clinical trials undertaken in populations
cortex, the cerebellum, and the hippocampus that of DS patients.
showreducedvolumespeciallycerebellum.During
theprenatalperiod,mouseandhumanstudieshave
shown altered corticogenesis in trisomic mouse Clinical trials in DS patients related with drugs
models(HaydarandReeves,2012)andanaltered used for the treatment of AD
cortical lamination in fetal brains. (Golden and
Hyman, 1994), smaller dendritic tree of pyramidal Intermsofcognitivesymptoms(notbrainpathol-
neurons (Benavides-Piccione et al., 2004), and a ogy),theprevalenceofAD inpatientswithDSis
smaller and hypocellular hippocampal dentate quitehigh.Itisimportanttonotethatpeoplewith
gyrus.Postnatally,theDSbrainexhibitsdegenera- DS tend to present with AD at a much younger
tion of cortical pyramidal neurons (Schmidt-Sidor age than the normal population as well as having
et al., 1990), profound dendrite and synapses subtle differences in physiology (e.g., metabolism
abnormalities(Beckeretal.,1986),andhypocellular and heart rate) and may therefore have different
hippocampus (Ferrer and Gullotta, 1990). The requirements from the general population. Up to
adult brain presents reduced numbers of granule 10%ofDSpatientsages30–39alsohavediagnos-
cells, increased astrocytosis (see Lott and Dierssen able AD. Between ages 40 and 49 the rate is as
forreview)andneurodegenerationofthecholiner- high as 25% and in ages 50–59 the prevalence is
gic and noradrenergic systems (see Lott and 55%. AD rates as high as 75% may occur in
Dierssen,2012). patients between the ages of 60 and 69.3. For
DSsubjectsdisplayseveralmorphologicalfeatures comparison, AD occurs in about 14% of people
thatcanbemildanddonotconstituteahallmarkof older than 65 in the general population.
the condition and a number of malformations and NotsurprisinglymanyclinicaltrialsinDSpatients
complications including cognitive impairment havebeenorientedattestingdrugsactingonaltered
(intellectual disability, see also Chapter 7), heart neurotransmissionsystemsinAD.Mostofthemare
defects, digestive malformations, congenzxital cata- currentlyinuseintherapeuticsofAD,likeacetylcho-
ract,Hirschsprungdisease,Westsyndrome,seizures, linesterase inhibitors (donepezil, rivastigmine,
leukemia,sleepapnea,sensorydeficiencies,autoim- galantamine), gabaergic (GABAA) antagonists
muneandendocrinepathologies,earlieraging,and (e.g., pentylenetetrazol), and N-methyl-D-aspartate
anAlzheimer-typeneuropathology.Despitemedical (NMDA) receptor antagonists (memantine)
interventions in DS have resulted in a significant (Prasher,2004).Theevaluationofthesetreatments
increase of life expectancy of DS, cognitive and isnotonlyjustifiedonabasisofahigherprevalence
behavioralfeaturesstillexertahardimpactontheir ofADlikeneuropathologyinDSsubjectsbutalsoon
functional ability throughout life. The the fact that AD and several neurodevelopmental
neurocognitive profile of individuals with DS is diseaseslikeDSsharecommonmolecularpathways
characterized by a remarkable deficit in learning/ andbrainalterations.Forthesereasons,thesedrugs
memoryandlanguageabilities.Theintelligencequo- have been evaluated not only in DS demented
tient (IQ) scale of patients with DS generally fall patientsbutalsoinDSnondementedpatients.
Table1. SummaryofmainclinicaltrialsperformedinDSsubjects
Drug Dose Design Patients Evaluations Outcome Reference
Donepezil 5mg(6weeks)and Openlabel 4DSadults Vinelandadaptivebehavior Someimprovement Kishnani
10mgupto9months (2demented) scales(VABS) first3months etal.(1999)
5mg(4weeks)and Randomized, 30DS Dementiascaleformentally Inconclusive Prasheretal.
10mgupto6months doubleblind demented retardedpersons(DMR) (2002)
placebo 16donepezil Neuropsychiatryinventory
controlled and (NPI)
14placebo Adaptativebehaviorscale
(ABS)
Severeimpairmentbattery
5mg(6weeks)and Openlabel 6DS Testofproblemsolving-TOPS Someimprovementin Helleretal.
10mgupto6months nondemented Clinicalevaluationoflanguage languageperformance (2003)
fundamentals-revised-CELF-R
2.5–10mgupto Openlabel 25DS Dementiascaleformentally Significantlyless Prasheretal.
2years demented retardedpersons(DMR) deteriorationinglobal (2003)
Neuropsychiatryinventory functioningand
(NPI) adaptivebehaviorin
Adaptativebehaviorscale DSadultswithDAD
(ABS)severeimpairment
battery
2.5mg(8weeks)and Openlabel 7DS(8–13 Testofproblemsolving-TOPS Someimprovementin Helleretal.
5mgupto8weeks yearsrange) Clinicalevaluationoflanguage languageperformance (2004)
fundamentals-revised-CELF-R
2.5mg(8weeks)and Openlabel 7DS(8–13 Visualattention,memoryfor Improvementin Spiridigliozzi
5mgupto8weeks yearsrange) names memory(NEPSY etal.(2007)
finalevaluationat22 Narrativememorysubtests memoryfornamesand
weeks fromtheNEPSY narrativememory)
Conners’parentratingscales- andsustained
revisedvinelandadaptive attentiontotasks
behaviorscales(VABS) (Conners’parent
ratingscales)
5mg(6weeks)and Randomized, Nondemented Severeimpairmentbattery Efficacyinsomebut Kishnani
10mg(6weeks) doubleblind patients (SIB) notallsubjects etal.(2009)
placebo (18–35years) Rivermeadbehavioralmemory
controlledwith 123double Testforchildren(RBMT-C)
openlabel blind87open- Clinicalevaluationoflanguage
extension label fundamentals(CELF-3)
2.5–10mg(2.5mg/ Randomized, 129DS Vineland-IIadaptivebehavior Nobenefit Kishnani
weekescalation) doubleblind patients scales(VABS-II) demonstrated etal.(2010)
(10weeks) placebo (10–17years) Parent/Caregiverratingform
controlled (PCRF)
(Continued)
Table1. SummaryofmainclinicaltrialsperformedinDSsubjects(Continued)
Drug Dose Design Patients Evaluations Outcome Reference
Rivastigmine 1.5–12mgescalationin Openlabel 17DS Dementiascaleformentally Inconclusive Prasheretal.
8weeks(24weeks) comparison demented retardedpersons(DMR) (2005)
withapervious Neuropsychiatryinventory
placebogroup (NPI)
(Prasheretal., Adaptativebehaviorscale
2002) (ABS)
4.5mg Openlabel20 10DSpatients Vinelandadaptivebehavior Noimprovementin Helleretal.
weeksfollow- (meanage scales(VABS) cognitiveandlanguage (2010)
up28weeks 15years) Clinicalevaluationoflanguage performance
fundamentals(CELF-3)
LeiterInternational
performancescalerevised
(Leiter-R)
Memorysubtestsfromthe
NEPSY
Folinicacid Selenium10mg,zinc Randomized 156DS Griffithsdevelopmental Noevidenceto Ellisetal.
vitaminsand 5mg,vitaminA0.9 controlledtrial patients quotientMacArthur supporttheuseof (2008)
minerals mg,vitaminE100mg, with2(cid:2)2 <7months communicativedevelopment antioxidantsorfolinic
andvitaminC50mg, factorial inventoryat18monthsafter acidsupplementsin
folinicacid0.1mg,for design, startingsupplementation DSchildren
18months balancedwith
placedo:
folinicacid
versus
antioxidants
versusfolinic
acidþ
antioxidants
versusplacebo
Acetyl-L- 10mg/kg/day(1st Randomized, 40DSpatients Stanford–BinetIntelligence Noimprovementin Pueschel
carnitine month)20mg/kg/day doubleblind (18–30years) ScaleHiskey–NebraskaVisual cognitionand (2006)
(2ndmonth)30mg/kg/ placebo AttentionSpanandMatching functioning
day(restofstudy) controlled FamiliarFiguretestsMazes
andCodingsubtests(WISC)
Riddlessubtest(KABC)
Comprehensionsubtest
(WISC)VinelandAdaptive
BehaviorScales(VABS)Child
BehaviorChecklist
5
Cholinergic neurotransmission ofadirectnicotinicstimulationincognitiveperfor-
mance has been examined in a very limited num-
Neuropathological and neurochemical similarities ber of DS patients. Results are conflicting and
betweenDSandADdiseasearewellestablished, improvements in attention and information pro-
amongthem,thereisalossofcholinergicinputto cessing have been reported in some subjects
cortical and limbic areas in both disorders. Cho- (Bernertetal.,2001;Seidletal.,2000).
linergic deficits have been linked to the cognitive
(memory) and adaptive impairments in AD, and
Inhibitors of acetylcholinesterase
acetylcholinesterase inhibitors, such as donepezil
hydrochloride, are proven symptomatic therapies
Pilot studies in DS and AD patients supported
improving cognitive performance and quality of
the view that the selective anticholinesterase
life in individuals with dementia and AD.
inhibitor donepezil has some benefit (improve-
Pioneering studies already suggested that there
ment in dementia scores) in mild to moderate
was some potential in using this drug in DS
AD patients. A number of side effects did occur
patients (Kishnani et al., 1999).
including diarrhea, insomnia, fatigue, and nausea
(Lott et al., 2002; Prasher et al., 2002).
Acetyl-L-carnitine Donepezil has been evaluated not only in DS
andADpatientsbutalsoinnondementedDSadult
Acetyl-L-carnitine,derivedfromcarnitine,hasbeen patientsandinDSchildren.Studiesevaluatedcog-
reportedtodisplaypropertieswhichmaybebenefi- nitiveperformancebutweremainlyfocusedinthe
cial in AD. These include activity at cholinergic treatmentoflanguage deficits(Helleretal.,2003,
neurons, membrane stabilization, and mitochon- 2004; Johnson et al., 2003; Kishnani et al., 2009).
drial antioxidant activity (Palacios et al., 2011). With the exception of one area (language), no
Preliminary studies suggested a beneficial effect improvement was noted in any of the cognitive
of acetyl-L-carnitine on cognition and behavior in subtests, behavioral scores, or caregiver ratings.
aging subjects. However, the evidence does not Increased irritability and/or assertiveness were
suggest that acetyl-L-carnitine is likely to prove an noted in some DS children (Spiridigliozzi et al.,
important therapeutic agent (Hudson and 2007).Inarecentreport,donepezilversusplacebo
Tabet,2003). failedtodemonstrateanybenefitincognitiveper-
Acetyl-L-carnitinehasbeenadministeredtoDS formance in children and adolescents with DS
patients and significant improvements of visual (Kishnanietal.,2010).AJapanesestudyneverthe-
memory and attention were reported (De Falco lessreportedimprovementsinmentalfunctioning
etal.,1994).Inamorerecentdouble-blindclinical in females DS patients with severe cognitive
trialwith40individualswithDS,acetyl-L-carnitine impairment,raisingthequestiononwhetherthere
was administered during a 6-month period with are gender differences in the efficacy of the drug
psychological evaluations at baseline and at 3, 6, (Kondohetal.,2011).
and 9 months. No improvement in cognitive Rivastigmine, an inhibitor of acetylcholinester-
functions was found (Pueschel, 2006). ase,hasalsobeenevaluatedinDSpatients(Heller
etal.,2010;Prasheretal.,2005).Resultsaresimilar
Nicotine tothosereportedfordonepezil,suggestingthatthe
long-term use of rivastigmine does not improve
The rationale for administering nicotine in the cognitiveandlanguageperformance.
form of a transdermal patch are similarities Galantamine is a competitive and reversible
between DS and AD, particularly cholinergic cholinesterase inhibitor and an allosteric ligand
deficits(Fodaleetal.,2006).Thepotentialactivity at nicotinic acetylcholine receptors. It is used for
