1. Inherited Disorders of Human Memory – Mental Retardation Syndromes
Chapter 11:
Inherited Disorders of Human Memory – Mental Retardation Syndromes
From Mechanisms of Memory, second edition
By J. David Sweatt, Ph.D.

2. Chapter 11: Mental Retardation Syndromes

3. Table I: Mouse Models of Human Mental Retardation Syndromes
Gene Product
Potential Targets
Mouse Model
References
Learning 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?

4. Table I: Mouse Models of Human Mental Retardation Syndromes Continued
Fragile X Mental
FMR1 Protein (RNA
protein synthesis + ?
Bardoni et al (17)
Retardation 1
binding proteins)
machinery,
(strain
mRNA targeting,
dependent)
spine structure, LTD
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

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

6. Signaling Pathways Implicated in Human Memory Formation
Figure 1

7. Signal Transduction Pathways Involved in Learning and Memory
G Protein
ERK1/2
MEK1/2
Raf1 R1
Grb
SOS
Ras
PKC R2
B-Raf
PKA R3
Rap AC
Gene
Expression
Mnk1/2
eIF4E
Protein
Synthesis
MAPs
Spine
Structure
CRE
CREB P
CBP
RSK2
GEF
NF1
GAP
Neurofibromatosis MR
NO.
Ca2+
Nucleus R4
Coffin-Lowry Syndrome
Rubinstein-Taybi
Syndrome
Fragile X Syndrome
Figure 2

8. Ras-Dependent spacial learning deficits in NF1
K-ras
N-ras
Farnesyl Transferase Inhibitor
Figure 3

9. Ras-Dependent LTP deficits in NF1
Figure 4

10. Complex Formation Step 3
Ubiquitination Pathway of Proteins
Step 1
Step 2
Complex Formation Step 3
Step 4
Step 5
E1 Charging
E2 Charging
E2—E3
Transfer
Target
Poly-Ubiquitination
Figure 5

11. Selective Deficit in Context-Dependent Fear Conditioning in Ube3a Maternal Deficient Mice
Figure 6

12. Impairment of Hippocampal LTP in Ube3a Maternal Deficient mice
Figure 7

13. Fragile X Mental Retardation Syndrome
Current Model of Fragile X Mental Retardation
Coding Region
Regulatory Region
CGG Expansion in Regulatory Region
Point Mutation in Coding Region
Disruption
Of FMR1 Gene
Loss of
FMR1 Protein (FMRP)
FMR1/FXR
Interaction domain
Ribosome
Interaction
Domain
RGG Box KH
RGG Box = Arginine & Glycine-rich domain
KH domain = Ribonucleoprotein K homology domain
FMRP = 63K RNA binding protein that binds to poly (G) and poly (U) structures
FMR1 Gene
Gene
Structure
FMRP
Figure 8

14. DHPG Induces Greater LTD of Synaptic Responses in Hippocampus
Brief application of the mGluR agonist DHPG (5 min; 100 μM) induces greater LTD of synaptic responses in hippocampus of Fmr1-KO mice as compared with WT littermate controls. (A1) Plotted are average (±SEM) FP slope values over the time course of the experiment. In Fmr1-KO animals, the response 60 min after treatment was depressed to 77 ± 3% of preDHPG baseline (n = 21 slices from 9 mice; open circles); in interleaved WT controls, the response was depressed to 88 ± 4% of baseline (n = 15 slices from 8 mice; filled circles; different at P = 0.02; t test). (A2) Representative FPs (2 min average) taken at the times indicated by the numbers on the graph. (Bar = 1 mV; 5 msec.) (B) Cumulative probability distributions of FP slope values (% of baseline), measured 1 h after DHPG in individual slices from both KO and WT groups. The distribution in KO mice is significantly different from that in WT mice as determined by Kolmolgarov–Smirnov test (P < 0.05).
Figure 9

15. Role of mGluR5 in Fragile X Mental Retardation
Model. Previous research has shown that activation of mGluR5 stimulates the internalization of AMPA receptors and NMDARs (not shown; ref. 11). The stable expression of this modification requires protein synthesis, which we propose is negatively regulated by FMRP synthesized in response to mGluR activation. Therefore, in the absence of FMRP, LTD magnitude is increased.
Figure 10

16. Enhanced LTP in FMR2 Knockout Mice
-20
-10 10 20 30 40 50 60
100
150
200
250
Mutant
Wildtype
Time (min)
Slope fEPSP
(Standardized to Baseline)
Figure 11

17. Actin Cytoskeleton—Loss of LIMK-1 causes increased actin turnover
Williams Syndrome
rho
PAK, ROCK
LIMK-1
(Williams Syndrome)
Actin Depolymerization Factor (ADF) / cofilin
Actin Cytoskeleton—Loss of LIMK-1
causes increased actin turnover
Altered Dendritic Spine
Augmented LTP, Learning Impairments
rac
PKC
Direct phosphorylation
(inhibitory)
ADF / Cofilin promotes
Actin depolymerization
Blue Box 3

18. Non-Syndromic X-Linked Mental Retardation
Rho
PAK3 (p21 Activated Kinase)
JNK p38
Cytoskeleton
raf-1
LTD disruption?
Dbl (Diffuse B-cell Lymphoma)
Rho GEF6
Rho GAP
Rho GDI
GEFs + _
Blue Box 4