From Mechanisms of Memory, second editionBy J. David Sweatt, Ph.D.

Chapter 11:Inherited Disorders of Human Memory – Mental Retardation

Syndromes

Chapter 11: Mental Retardation Syndromes

Table I: Mouse Models of Human Mental Retardation Syndromes

Human Mental Retardation Syndromes

Gene Product Potential Targets

Mouse Model

ReferencesLearning Defects?

LTP Change?

Neurofibromatosis Neurofibromin 1 (NF1) ras/ ERK + + Costa et al (4, 39)

    adenylyl cyclase     Tong et al (9) 

    cytoskeleton      

           

Coffin-Lowry Ribosomal S6 Kinase2 CREB + ? Dufresne et al (12) 

Syndrome (rsk2) ribosomal S6 protein     Harum et al (13)

           

Angelman Syndrome

Ubiquitin Ligase (E6AP) p53 tumor suppressor + + Jiang et al (40)

    protein, others?      

Fragile X Mental FMR1 Protein (RNA protein synthesis + ?

Bardoni et al (17)

Retardation 1 binding proteins) machinery, (strain    

    mRNA targeting,dependen

t)    

    spine structure, LTD      

           

Fragile X Mental FMR2 protein Unknown-- + + Gu et al (41)

Retardation 2 (putative transcription Gene Expression      

  factor)      

           

Rett Syndrome Methyl-CpG Binding Transcriptional ? ?Shahbazian et al (23)

  Protein 2 (MeCP2) repressors--regulation      

    of unknown genes      

           

Myotonic Dystrophy Dystrophin Protein Na+ channels, ? ? Mistry et al (42) 

  Kinase (DMPK) Tau, many others      

Table I: Mouse Models of Human Mental Retardation Syndromes

Continued

Myotonic Dystrophy Dystrophin Protein Na+ channels, ? ? Mistry et al (42) 

  Kinase (DMPK) Tau, many others      

           

Down Syndrome DS critical locus Multiple genes including + + Siarey et al (36)

(Trisomy 21)   DYRK1A and SOD      

           

  DYRK1A (minibrain unknown + ? Altafaj et al (35)

  kinase homolog)      

           

  Superoxide Dismutase Superoxide dependent + + Gahtan et al (43)

  (SOD) processes--redox      

    regulation of PKC, ras,      

    transcription factors      

           

Williams Syndrome WS critical locus: cytoskeleton + + Morris et al (44)

  LIMK-1 extracellular matrix      

  Elastin spine morphology      

  Syntaxin 1A      

  FKBP6      

  EIFH4      

Table I: Mouse Models of Human Mental Retardation Syndromes Cont.

Figure 1

Signaling Pathways Implicated in Human Memory Formation

Figure 2

G Protein

ERK1/2

MEK1/2

Raf1

R1Grb

SOSRas

PKC

R2

B-Raf

PKA

R3

Rap

AC

Gene Expression

Mnk1/2

eIF4E

Protein Synthesis

MAPs

Spine Structure

CRECREB

P

CBP

RSK2

GEF

NF1GAP

Neurofibromatosis MR

NO.

Ca2+

NF1

Ca2+

Nucleus

R4

Coffin-Lowry Syndrome

Rubinstein-TaybiSyndrome

Fragile X Syndrome

Signal Transduction Pathways Involved in Learning and Memory

Fig

ure

3

K-ras

N-ras

Farnesyl Transferase Inhibitor

Ras-Dependent spacial learning deficits in NF1

Figure 4

Ras-Dependent LTP deficits in NF1

Figure 5

E 1

E 1E 1

UbUb

ATP

E2L i g a s eUb

E3Lig as e

Targe tPro te in

E 2Ub

E 3 Targe tPro te in

Ub

Ub Ub

UbUb

Ub

Step 1

Step 2

Complex Formation

Step 3

Step 4

Step 5

E1 Charging

E2 Charging

E2—E3 Transfer

TargetPoly-

Ubiquitination

Ubiquitination Pathway of Proteins

Figure 6

Selective Deficit in Context-Dependent Fear Conditioning in Ube3a Maternal Deficient Mice

Figure 7

Impairment of Hippocampal LTP in Ube3a Maternal Deficient mice

Figure 8

Current Model of Fragile X Mental RetardationCoding Region

Regulatory Region

CGG Expansion in Regulatory Region

Point Mutation in Coding Region

DisruptionOf FMR1 Gene

Loss ofFMR1 Protein (FMRP)

FMR1/FXRInteraction domain

RibosomeInteraction

Domain

RGG BoxKHDomain

KHDomain

RGG Box = Arginine & Glycine-rich domainKH domain = Ribonucleoprotein K homology domain

FMRP = 63K RNA binding protein that binds to poly (G) and poly (U) structures

FMR1 GeneGeneStructure

FMRPStructure

Fragile X Mental Retardation Syndrome

Figure 9

DHPG Induces Greater LTD of Synaptic Responses in Hippocampus

Figure 10

Role of mGluR5 in Fragile X Mental Retardation

Figure 11

A

-20 -10 0 10 20 30 40 50 60

50

100

150

200

250

Mutant

Wildtype

Time (min)

Slo

pe

fE

PS

P

(Sta

nd

ard

ize

d t

o B

as

eli

ne

)

Enhanced LTP in FMR2 Knockout Mice

rho

PAK, ROCK

LIMK-1(Williams Syndrome)

Actin Depolymerization Factor (ADF) / cofilin

Actin Cytoskeleton—Loss of LIMK-1causes increased actin turnover

Altered Dendritic Spine

Augmented LTP, Learning Impairments

rac PKC

Direct phosphorylation(inhibitory)

ADF / Cofilin promotesActin depolymerization

Blue Box 3

Williams Syndrome

Rho

PAK3 (p21 Activated Kinase)

JNK p38

Cytoskeletonraf-1LTD disruption?

Dbl (Diffuse B-cell Lymphoma)Rho GEF6

Rho GAPRho GDI

GEFs+ _

Blue Box 4

Non-Syndromic X-Linked Mental Retardation