Inherited Disorders of Human Memory:

Mental Retardation Syndromes

From Mechanisms of Memory by J. David Sweatt, Ph.D.

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

CRE

CREB

P

CBP

RSK2

GEF

NF1GAP

Neurofibromatosis MR

NO.

Ca2+

G Protein

NF1

Ca2+

Nucleus

R4

Coffin-Lowry Syndrome

Rubinstein-TaybiSyndrome

Fragile X Syndrome

PO4

ras rasGDP GTP

GTP

GTP Hydrolysis

GAPsGTPase Activating Proteins

e.g. NF1, SynGAP

GEFsGuanine Nucleotide

Exchange Factor Proteins

e.g. SOS, cAMP GEF,

Ca2+/DAG GEF, ras GRF

Inactive Active

++

Activation of ras

Weeber and Sweatt. Neuron 33:845-848.

K-ras

N-ras

Farnesyl Transferase Inhibitor

Costa et al (2002) Nature 415:526-530.

Ras-dependent Spatial Learning in Nf1+/- Animals

Ras-dependent LTP deficits in Nf1+/- animals

Costa et al (2002) Nature 415:526-530.

The Ubiquitination Pathway

Step 1

Step 2

Complex Formation

Step 3

Step 4

Step 5

E1 Charging

E2 Charging

E2—E3 Transfer

TargetPoly-

Ubiquitination

E1

E1E1

Ub Ub

ATP

E2LigaseUb

E3Ligase

TargetProtein

E2Ub

E3 TargetProtein

UbUb Ub

UbUb

Ub

Weeber and Sweatt (2000) Recent Res. Devel. Neurochem. 3:289-299.

Selective Deficit in Context-dependent Fear conditioning in Ube3a Maternal Deficient Mice

Jiang et al (1998) Neuron 21:799-811.

Impairment of hippocampal LTP in Ube3a Maternal Deficient mice

Jiang et al (1998) Neuron 21:799-811.

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

Enhanced LTP in FMR2 knockout mice

A

C D-20 -10 0 10 20 30 40 50 60

50

100

150

200

250

MutantWildtype

Time (min)

Slop

e fE

PSP

(Sta

ndar

dize

d to

Bas

elin

e)

Time (min)

B

-20 -10 0 10 20 30 40 50 6050

100

150

200

250

WildtypeMutant

Slop

e fE

PSP

(Sta

ndar

dize

d to

Bas

elin

e)

-20 -10 0 10 20 30 40 50 60 70 800

100

200

300

MutantWildtype

Time (min)

Slop

e fE

PSP

(Sta

ndar

dize

d to

Bas

elin

e)

-30 -20 -10 0 10 20 30 40 50 6050

100

150

200

WildtypeMutant

Time (min)

Slop

e fE

PSP

(Sta

ndar

dize

d to

Bas

elin

e)

Gu et al. (2002) J. Neurosci. 22:2753-2763.

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

Williams Syndrome

Rho

PAK3 (p21 Activated Kinase)

JNK p38

Cytoskeletonraf-1LTD disruption?

Dbl (Diffuse B-cell Lymphoma)Rho GEF6

Rho GAPRho GDI

GEFs+ _

Nonsyndromic X-Linked Mental Retardation