1. Inherited Disorders of Human Memory: Mental Retardation Syndromes From Mechanisms of Memory by J. David Sweatt, Ph.D.

2. ERK1/2 MEK1/2 Raf1 R1R1 Grb SOS Ras PKC R2R2 B-Raf PKA R3R3 Rap AC Gene Expression Mnk1/2 eIF4E Protein Synthesis MAPs Spine Structure CRE CREB P CBP RSK2 GEF NF1 GAP Neurofibromatosis MR NO. Ca 2+ G Protein NF1 Ca 2+ Nucleus R 4 Coffin-Lowry Syndrome Rubinstein-Taybi Syndrome Fragile X Syndrome

3. PO 4 ras GDPGTP GTP Hydrolysis GAPs GTPase Activating Proteins e.g. NF1, SynGAP GEFs Guanine Nucleotide Exchange Factor Proteins e.g. SOS, cAMP GEF, Ca 2+ /DAG GEF, ras GRF InactiveActive + + Activation of ras Weeber and Sweatt. Neuron 33:845-848.

4. K-ras N-ras Farnesyl Transferase Inhibitor Costa et al (2002) Nature 415:526-530. Ras-dependent Spatial Learning in Nf1 +/- Animals

5. Ras-dependent LTP deficits in Nf1 +/- animals Costa et al (2002) Nature 415:526-530.

6. The Ubiquitination Pathway Step 1 Step 2 Complex Formation Step 3 Step 4 Step 5 E1 Charging E2 Charging E2—E3 Transfer Target Poly- Ubiquitination E1 Ub ATP E2 Ligase Ub E3 Ligase Target Protein E2 Ub E3 Target Protein Ub Weeber and Sweatt (2000) Recent Res. Devel. Neurochem. 3:289-299.

7. Selective Deficit in Context-dependent Fear conditioning in Ube3a Maternal Deficient Mice Jiang et al (1998) Neuron 21:799-811.

8. Impairment of hippocampal LTP in Ube3a Maternal Deficient mice Jiang et al (1998) Neuron 21:799-811.

9. 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 Domain KH Domain 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 Structure

10. Enhanced LTP in FMR2 knockout mice Gu et al. (2002) J. Neurosci. 22:2753-2763.

11. 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 Williams Syndrome

12. Rho PAK3 (p21 Activated Kinase) JNK p38 Cytoskeletonraf-1LTD disruption? Dbl ( Diffuse B-cell Lymphoma) Rho GEF6 Rho GAP Rho GDI GEFs + _ Nonsyndromic X-Linked Mental Retardation