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

1. 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

4. Table I: Mouse Models of Human Mental Retardation SyndromesContinued

5. Table I: Mouse Models of Human Mental Retardation SyndromesCont.

6. Signaling Pathways Implicated in Human Memory Formation Figure 1

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

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

9. Ras-Dependent LTP deficits in NF1 Figure 4

10. E1 Charging Step 1 Step 2 E2 Charging E2—E3 Transfer Step 4 Complex Formation Step 3 Target Poly-Ubiquitination Step 5 Ubiquitination Pathway of Proteins 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. Current Model of Fragile X Mental Retardation Coding Region Regulatory Region Gene Structure FMR1 Gene CGG Expansion in Regulatory Region Point Mutation in Coding Region Disruption Of FMR1 Gene Loss of FMR1 Protein (FMRP) FMRP = 63K RNA binding protein that binds to poly (G) and poly (U) structures FMRP Structure KH Domain KH Domain FMR1/FXR Interaction domain Ribosome Interaction Domain RGG Box RGG Box = Arginine & Glycine-rich domain KH domain = Ribonucleoprotein K homology domain Fragile X Mental Retardation Syndrome Figure 8

14. DHPG Induces Greater LTD of Synaptic Responses in Hippocampus Figure 9

15. Role of mGluR5 in Fragile X Mental Retardation Figure 10

16. A 250 200 150 Slope fEPSP (Standardized to Baseline) 100 Wildtype Mutant 50 -20 -10 0 10 20 30 40 50 60 Time (min) Enhanced LTP in FMR2 Knockout Mice Figure 11

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

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